Novel piperidine derivative

ABSTRACT

Provided are a histamine-H3 receptor antagonist; and a preventive and/or a remedy for metabolic system diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, circulatory system diseases, for example, stenocardia, acute/congestive cardiac insufficiency, cardiac infarction, coronary arteriosclerosis, hypertension, nephropathy, sleep disorder and various diseases accompanied by sleep disorder such as idiopathic hypersomnia repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, night worker sleep insanitation, idiopathic insomnia, repetitive insomnia, true insomnia, electrolyte metabolism disorder; and central and peripheral nervous system diseases such as bulimia, emotional disorder, melancholia, anxiety, epilepsy, delirium, dementia, shinzophrenia, attention deficit/hyperactivity disorder, memory disorder, Alzheimer&#39;s disease, Parkinson&#39;s disease, sleep disorder, recognition disorder, motion disorder, paresthesia, dysosmia, epilepsy, morphine resistance, narcotic dependency, alcoholic dependency. The histamine-H3 receptor antagonist comprises a piperidine derivative compound of formula (I) [wherein X 1  and X 2  independently represent a nitrogen atom or CH; Y represents a specific group; X 3  represents O s —(CH 2 ) m ; R 1  and R 2  independently resent a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkoxy group, or an acetyl group substituted with 2 or 3 fluorine atoms; s is 0 or 1; and m is an integer to make (m+s) 0 or from 1 to 4], or its pharmaceutically-acceptable salt.

TECHNICAL FIELD

The present invention relates to a novel piperidine derivative, to ahistamine-H3 receptor antagonist containing the novel piperidinederivative as an active ingredient thereof, and to a preventive orremedy for metabolic system diseases, circulatory system diseases,central or peripheral nervous system diseases.

BACKGROUND ART

It has been known that, in organisms such as typically mammals,histamine that is a physiologically-active endogenous factor functionsas a neurotransmitter and has extensive pharmacological activities (forexample, see Life Science, 17, 1975, 503 (1975)). Immunohistochemicalstudies have made it clear that a histamine-agonistic (producing) cellbody exists in the nodal papillary nucleus in a posterior hypothalamicregion and that histamine nerve fibers project histamine in an extremelybroad range in the brain, which supports various pharmacological effectsof histamine (for example, see Journal of Comprehensive Neurology, 273,283). The existence of histamine-agonistic nerves in the nodal papillarynucleus in a posterior hypothalamic region suggests that histamine mayhave an important role in control of physiological functions relating tobrain functions, especially to hypothalamic functions (sleep, vigilancerhythm, incretion, eating and drinking action, sexual action, etc.) (forexample, see Progress in Neurobiology, 63, 637 (2001)). The existence ofhistamine projection to the brain region that relates to vigilancesustenance, for example, to cerebral cortex suggests the role ofhistamine in control of vigilance or vigilance-sleep cycle. Theexistence of histamine projection to many peripheral structures such ashippocampus and amygdaloid complex suggests the role of histamine incontrol of autonomic nerves, emotion, control of motivated action andleaning/memory process.

On the other hand, when released from producing cells, histamine actswith a specific polymer that is referred to as a receptor on the surfaceof a cell membrane or inside a target cell, therefore exhibiting itspharmacological effects for control of various body functions.Heretofore, four types of histamine receptors (H1 to H4) have beenfound. In particular, the presence of a histamine receptor thatparticipates in the central and peripheral nervous functions, ahistamine-H3 receptor, has been shown by various pharmacological andphysiological studies (for example, see Trends in PharmacologicalScience, 8, 24 (1986)); and recently, human and rodent histamine-H3receptor genes have been identified and their existence has been madeclear (for example, see Molecular Pharmacology, 55, 1101 (1999)). It isshown that a histamine-H3 receptor exists in the presynaptic membrane ofcentral or peripheral neurocytes and functions as a self-receptor,therefore controlling the liberation of histamine and controlling therelease of other neurotransmitters Specifically, it is reported that ahistamine-H3 receptor agonist or its antagonist or inverse-agonist(generically referred to as antagonist) controls the release ofhistamine, noradrenaline, serotonin, acetylcholine or dopamine fromnerve ending. For example, the release of these neurotransmitters isinhibited by an agonist such as (R)-(α)-methylhistamine, and the releaseof these neurotransmitters is promoted by an antagonist orinverse-agonist such as thioperamide (for example, see Trends inPharmacological Science, 19, 177 (1998)). Recent studies have shown thata histamine-H3 receptor has extremely high homeostatic activities(endogenous agonistic factor, e.g., activity observed in the absence ofhistamine) in the receptor-expressing cells/tissues or in a membranefraction derived from the expressing cells/tissues and even in livingbodies (for example, see Nature, 408, 860). It is reported that thesehomeostatic activities are inhibited by an antagonist or aninverse-agonist. For example, a homeostatic self-receptor activity isinhibited by thioperamide or syproxyfan, and, as a result, the releaseof neurotransmitters from nerve ending, for example, the release andliberation of histamine from it is thereby promoted.

Various studies have been made for clarifying the effects of ahistamine-H3 receptor. In animal experiments with rats, a high-levelselective inhibitor of histamine synthase (histidine decarboxylase)inhibits the vigilance of rats, which suggests that a histamine-H3receptor may function for controlling motive vigilance. Administrationof a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to catsincreases their deep slow-wave sleep (for example, see Brain Research,523, 325 (1990)). Contrary to this, it has been clarified that ahistamine-H3 receptor antagonist or inverse-agonist, thioperamidedose-dependently increases vigilance, and decreases slow-wave and REMsleep (see Science, 48, 2397 (1991)). This suggests that a histamine-H3receptor may participate in control of vigilance-sleep, and suggests apossibility that a selective histamine-H3 receptor agonist, or itsantagonist or inverse-agonist may be useful for treatment of sleepdisorders. Further, in animal experiments with rats, administration ofhistamine to the ventricle of rats inhibited their eating action,therefore suggesting that histamine may participate in control of eatingaction (for example, see Research, 793, 279 (1998)), and it has beenclarified that thioperamide dose-dependently inhibits eating action andpromotes intracerebral histamine liberation (for example, see LifeScience, 69, 469 (2001)). These informations suggest that a histamine-H3receptor may participate in eating action control, further suggesting apossibility that an a histamine-H3 receptor antagonist orinverse-agonist may be useful for prevention or remedy of metabolicdiseases such as eating disorder, obesity, diabetes, emaciation,hyperlipemia. In addition, in animal experiments with rats, it has beenclarified that administration of a histamine-H3 receptor agonist,(R)-(α)-methylhistamine to rats dose-dependently lowered their basaldiastolic pressure, and its action was antagonized by a histamine-H3receptor antagonist or inverse-agonist, thioperamide (for example, seeJournal of Physiology and Pharmacology, 49, 191 (1998)). Theseinformations suggest that a histamine-H3 receptor may participate incontrol of blood pressure, heart beat and cardiac output, furthersuggesting a possibility that a histamine-H3 receptor agonist or itsantagonist or inverse-agonist may be useful for prevention or remedy ofcirculatory system diseases such as hypertension and various cardiacdisorders.

It is reported that, in animal experiments with rats, administration ofa histamine-H3 receptor agonist, (R)-(α)-methylhistamine to rats loweredtheir object recognition and learning effects in the object recognitiontest and the passive turnout test with them, while on the other hand, inthe scopolamine-induced amnesia test with them, a histamine-H3 receptorantagonist or inverse-agonist, thioperamide dose-dependently relievedtheir amnesia induced by the chemical (for example, see BehaviouralBrain Research, 104, 147 (1999)). These informations suggest apossibility that a histamine-H3 receptor antagonist or inverse-agonistmay be useful for prevention or remedy of various diseases accompaniedby memory and learning disorder, for example, Alzheimer's disease,Parkinson's disease or attention deficit/hyperactivity disorder.Further, it has been clarified that, in animal experiments with rats, ahistamine-H3 receptor antagonist or inverse-agonist, thioperamidedose-dependently inhibited the spasm induced by electric shock or theepileptoid seizure induced by pentylene tetrazole (PTZ) (for example,see European Journal of Pharmacology, 234, 129 (1993) and Pharmacology,Biochemistry and Behavior, 68, 735 (2001)). These informations suggest apossibility that a histamine-H3 receptor antagonist or inverse-agonistmay be useful for prevention or remedy of epilepsy or central spasm. Inaddition, a histamine-H3 receptor antagonist or inverse-agonist,thioperamide or GT-2331 reduces emotional cataplexy and sleep ofnarcoleptic dogs (for example, see Brain Research, 793, 279 (1998)).

These information suggest that an H3 receptor may participate in controlof vigilance-sleep and sleep disorder-associated diseases, furthersuggesting a possibility that a selective histamine-H3 agonist or itsantagonist or inverse-agonist may be useful for treatment of sleepdisorders or various sleep disorder-associated diseases (for example,idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia,narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome,circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder,senile insomnia, night worker sleep insanitation, idiopathic insomnia,repetitive insomnia, true insomnia, melancholia, schizophrenia).

In animal experiments with rats, administration of a histamine-H3receptor antagonist or inverse-agonist thioperamide or GT-2331 to ratsrelieved the condition of learning disorder (LD) and attention deficithyperactivity disorder (ADHD) (for example, see Life Science, 69, 469(2001)).

These informations suggest a possibility that a selective H3-agonist orits antagonist or inverse-agonist may be useful for remedy and/orprevention of learning disorder or attention deficit hyperactivitydisorder.

There are known a novel imidazole derivative (for example, see JP-T10-501001) as a histamine-H3 receptor antagonist and/or agonist,4-(4(5)-imidazolyl)butyramidine, 2-(4)-imidazolylethylisothiourea or anN-methyl derivative thereof having an antagonistic activity against ahistamine-H3 receptor (for example, see JP-A-6-87742), or a migraineremedy, a tranquilizer, a hypnotic, an anesthetic, a sedative, ananxiolytic, an antiasthmatic, an antibronchitic and an antiinflammatoryagent that comprise N-methyl derivative thereof; and a histaminereceptor antagonist useful for remedy of allergic rhinitis, inflammatoryintestinal disorders, asthma, bronchitis and vomition that comprises anN-methyl-N-(4-piperidin-1-yl)-2-arylbutyl)benzamide (for example, seeJP-T-2002-504082).

However, no one knows that a piperidine derivative having a skeletonwith a nitrogen-containing cyclo-ring and a specific nitrogen-containingheteroaryl ring or phenyl group bonding to piperidine could be ahistamine-H3 antagonist, and no one also knows that the piperidinederivative could be effective for metabolic system diseases, circulatorysystem diseases, central or peripheral nervous system diseases, andespecially effective for relieving obesity.

DISCLOSURE OF THE INVENTION Problems That the Invention is to Solve

An object of the invention is to provide a novel piperidine derivative,and a histamine-H3 receptor antagonist comprising it and to provide apreventive or remedy for metabolic system diseases, circulatory systemdiseases, central or peripheral nervous system diseases, which isespecially effective for obesity and has few side effects.

We, the present inventors have assiduously studied on the assumptionthat a piperidine derivative may have an antagonistic effect or anadverse effect against a histamine-H3 receptor and could be ahistamine-H3 receptor antagonist, and, as a result, have found that aspecific piperidine derivative having a skeleton with a specificnitrogen-containing cyclo-ring and a specific nitrogen-containingheteroaryl ring or phenyl group bonding to the piperidine ring thereofare effective for relieving metabolic system diseases, circulatorysystem diseases, central or peripheral nervous system diseases, and havecompleted the invention.

Specifically, the invention relates to a compound of a general formula(I):

[in formula (I), X¹ and X² independently represent a nitrogen atom orCH; X³ represents O_(s)—(CH₂)_(m) (in which s indicates 0 or 1; mindicates an integer to make (m+s) 0 or 1 to 4); Y represents a group ofa general formula (II):

(in formula (II), j, k and l independently indicate 0 or 1; L₁represents a C1 to C4 lower alkylene group or a single bond; Mrepresents an oxygen atom or a group of a general formula (III):

(in formula (III), R⁰ represents a hydrogen atom or a C1 to C4 loweralkyl group); Q₁ represents a linear or branched lower alkyl group, anoptionally-condensed C3 to C9 cycloalkyl group, a phenyl group, anaphthyl group, or an optionally-condensed 3- to 8-membered heterocyclicgroup (the hetero ring may have from 1 to 3 hetero atoms selected from agroup consisting of an oxygen atom, a sulfur atom and a nitrogen atom),which is unsubstituted or has a substituent selected from a groupconsisting of a cyano group, a hydroxyl group, a lower alkyl group (thelower alkyl group may be further substituted with a hydroxyl group, ahalogen atom, an amino group, an aryl group or a heteroaryl group), acycloalkyl group, a lower alkoxy group (the lower alkoxy group may befurther substituted with a halogen atom), a halogen atom, a mono-loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoylgroup, a cycloalkyliminocarbamoyl group, a lactam ring, atrifluoromethyl group, a mono-lower alkylamino group, a di-loweralkylamino group and an alkanoyl group) (but excepting the following:1) a case where Y is an alkoxycarbonyl group, or2) a case where Y of formula (II) is a group of the following formula(II-1):

-L₁-O-Q₁  (II-1)

(in formula (II-1), L₁ and Q₁ have the same meaning as L₁ and Q₁ informula (II));R¹ and R² independently represent a hydrogen atom, a halogen atom, alinear or branched lower alkyl group, a lower alkoxy group, or an acetylgroup substituted with 2 or 3 fluorine atoms] (but excepting1-[4-(piperidin-1-yl)piperidin-1-yl]-4-(7-carbamoyl-1H-benzimidazol-2-yl)benzene,1-{4-(piperidin-1-yl)piperidin-1-yl}-4-(5-cyano-6-oxo-pyridin-2-yl)benzeneand1-{4-(pyrrolidin-1-yl)piperidin-1-yl}-4-(5-cyano-pyridin-2-yl)benzene)or its pharmaceutically-acceptable salt (claim 1).

The invention also relates to the compound or itspharmaceutically-acceptable salt of claim 1 wherein, in formula (I), R¹and R² are hydrogen atoms, m in X³ is an integer of from 1 to 3, and sis 0 (claim 2).

The invention further relates to the compound or itspharmaceutically-acceptable salt of claim 1 or 2, wherein, in formula(II), Y is a group of a general formula (IV):

in formula (IV), R³ is a hydrogen atom, or a lower alkyl group, and R⁴is a group of a general formula (V):

[in formula (V), R⁵ represents a hydrogen atom, a lower alkyl group, aC3 to C8 cycloalkyl group, an aralkyl group, or a heteroaryl group; nindicates 0 or an integer of from 1 to 4] (claim 3); or relates to thecompound or its pharmaceutically-acceptable salt of claim 1 or 2,wherein, in formula (II), Y is a group of a general formula (IV):

in formula (IV), R³ is a hydrogen atom, or a lower alkyl group, and R⁴is a group of a general formula (VI):

—(CH₂)_(q)-A  (VI)

[in formula (VI), A represents an aryl group, a heteroaryl group, acondensed bicyclic group of a C4 to C7 cycloalkyl group and an arylgroup, or a condensed bicyclic group of a C4 to C7 cycloalkyl group anda heteroaryl group; q indicates 0 or an integer of from 1 to 3] (claim4); or relates to the compound or its pharmaceutically-acceptable saltof claim 1 or 2, wherein, in formula (II), Y is a group of a generalformula (IV):

in formula (IV), R³ and R⁴ form a nitrogen containing heterocyclic groupas integrated with the nitrogen atom to which they bond (claim 5).

The invention also relates to the compound or itspharmaceutically-acceptable salt of claim 5, wherein thenitrogen-containing heterocyclic group is a monocyclic group such as apiperidinyl group, a pyrrolidinyl group, an azetidinyl group, ahomopiperidinyl group or a heptamethyleneiminyl group, or a bicyclicgroup of such a monocyclic group and a C4 to C7 cycloalkyl group, aphenyl group or a pyridyl group (claim 6); or relates to the compound orits pharmaceutically-acceptable salt of clans 3 to 6, wherein X¹ and X²are both CH₂, or one of them is a nitrogen atom (claim 7); or relates tothe compound or its pharmaceutically-acceptable salt of claim 1 or 2,wherein, in formula (II), Y is an aryl group or a 5-membered or6-membered heteroaryl group (the heteroaryl group has, in the ringthereof, from 1 to 3 hetero atoms selected from a group consisting of anitrogen atom, a sulfur atom and an oxygen atom), which is unsubstitutedor substituted with 1 or 2 substituents selected from a group consistingof a lower alkyl group, a lower alkoxy group, a hydroxyl group and ahalogen atom (claim 8); or relates to the compound or itspharmaceutically-acceptable salt of claim 8, wherein X¹ and X² are bothnitrogen atoms (claim 9); or relates to the compound or itspharmaceutically-acceptable salt of claim 1, wherein the piperidinederivative compound of formula (I) is any of the following (claim 10):

-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (1),-   N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (2),-   N-methyl-N-(1-cyclobutylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (3),-   N-methyl-N-(1-cyclopentylpiperidine-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (4),-   N-methyl-N-(1-cyclohexylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (5),-   N-methyl-N-(1-cyclohexylmethylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (6),-   N-methyl-N-[(3R)-1-cyclopentylpyrrolidin-3-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (7),-   N-methyl-N-[(3S)-1-cyclopentylpyrrolidin-3-yl)]-4-[4-piperidin-1-yl)piperidin-1-yl]benzamide    (8),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (9),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (10),-   N-(pyridin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    trifluoroacetate (11),-   2-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroisoquinoline    (12),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroquinoline    (13),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-4-phenylpiperazine (14),-   N-methyl-N-[1-(pyrimidin-2-yl)piperidin-4-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (15),-   N-methyl-N-(thiophen-2-yl)methyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (16),-   N-methyl-N-phenethyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (17),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-3-(3,4-difluorophenyl)pyrrolidine    (18),-   4-{-4-(piperidin-1-yl)piperidin-1-yl]benzylpiperidin-1-yl (19),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]benzamide    (20),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(azetidin-1-yl)piperidin-1-yl]benzamide    (21),-   N-methyl-N-(1-methylpiperidin-4-yl)-5-[4-(piperidin-1-yl)piperidin-1-yl]pyridine-2-carboxamide    (22),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(4,4-difluoropiperidin-1-yl)piperidin-1-yl]benzamide    (23),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5(4-cyanophenyl)pyrimidine    (24),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(3-pyridyl)pyrimidine (25),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3-trifluoromethylphenyl)pyrimidine    (26),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3,5-dichlorophenyl)pyrimidine    (27),-   2-[4-(piperidin-1-ylpiperidin-1-yl]-5-(2-naphthyl)pyrimidine (28),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-[4-(pyrrolidin-1-ylcarbonyl)phenyl]pyrimidine    (29),-   1-[4-(piperidin-1-yl)piperidin-1-yl]-4-(3-pyridyl)benzene (30),-   1 (piperidin-1-ylmethyl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzene    (31).

The invention also relates to a histamine-H3 antagonist orinverse-agonist containing, as the active ingredient thereof, a compoundor its pharmaceutically-acceptable salt of any of claims 1 to 10 (claim11); or relates to a preventive or remedy containing, as the activeingredient thereof, a compound or its pharmaceutically-acceptable saltof any of claims 1 to 10, which is for metabolic system diseases such asobesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fattyliver, circulatory system diseases, for example, stenocardia,acute/congestive cardiac insufficiency, cardiac infarction, coronaryarteriosclerosis, hype ion, nephropathy, sleep disorder and variousdiseases accompanied by sleep disorder such as idiopathic hypersomnia,repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodicacromotion disorder, sleep apnea syndrome, circadian rhythm disorder,chronic fatigue syndrome, REM sleep disorder, senile insomnia, nightworker sleep insanitation, idiopathic insomnia, repetitive insomnia,true insomnia, electrolyte metabolism disorder, and central andperipheral nervous system diseases such as bulimia, emotional disorder,melancholia, anxiety, epilepsy, delirium, dementia, shinzophrenia,attention deficit/hyperactivity disorder, memory disorder, Alzheimer'sdisease, Parkinson's disease, sleep disorder, recognition disorder,motion disorder, paresthesia, dysosmia, epilepsy, morphine resistance,narcotic dependency, alcoholic dependency (claim 12); or relates to amethod for producing a compound of a general formula (I-1), whichcomprise reacting a compound of a general formula (Ia):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (I); and L¹ represents a leaving group] and a compoundof a general formula (IIa):

Met-Y^(1p)  (IIa)

[wherein Met represents a metal atom-containing atomic group; and Y^(1p)has the same meaning as Y in a general formula (II):

or represents a group corresponding to it but protected at the aminogroup, the hydroxyl group or the carboxyl group therein], in thepresence of a catalyst to give a compound of a general formula (Ib):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (Ia); and Y^(1P) has the same meaning as Y^(1p) informula (IIa)], and optionally removing or converting the protectivegroup for the functional group of Y^(1p) to thereby produce a compoundof a general formula (I-1):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (Ib); and Y is a group derived from Y^(1p) in formula(Ib) by removing or converting the protective group for the functionalgroup of Y^(1p)] (claim 13); or relates to a method for producing acompound of a general formula (I-2), which comprises reacting a compoundof a general formula (Ic):

[wherein X¹ and X² have the same meanings as X¹ and X² in formula (I);Y^(1p) has the same meaning as Y in formula (n), or represents a groupcorresponding to it but protected at the amino group, the hydroxyl groupor the carboxyl group therein; and L² represents a leaving group] and acompound of a formula (Id):

[wherein R¹, R² and X³ have the same meanings as R¹, R² and X³ informula a)] under a basic condition or in the presence of a catalyst togive a compound of a general formula (Ie):

[wherein X¹, X² and Y^(1p) have the same meanings as X¹, X² and Y^(1p)in formula (Ic); X³, R¹ and R² have the same meanings as X³, R¹ and R²in formula (Id)], and optionally removing or converting the protectivegroup for the functional group of Y^(1p) to thereby produce a compoundof a general formula (I-2):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (Ie); and Y is a group derived from Y^(1p) in formula(Ie) by removing or converting the protective group for the functionalgroup of Y^(1p)] (claim 14); or relates to a method for producing acompound of a general formula (I-3), which comprises reacting a compoundof a general formula (If):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (I); Met represents a metal atom-containing atomicgroup] and a compound of a general formula (IIb):

Y^(1p)-L²  (IIb)

[wherein Y^(1p) has the same meaning as Y in a general formula (II), orrepresents a group corresponding to it but protected at the amino group,the hydroxyl group or the carboxyl group therein; and L² represents anordinary leaving group] to give a compound of a general formula (Ig):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (If); and YIP has the same meaning as Y^(1p) informula (IIb)], and optionally removing or converting the protectivegroup for the functional group of Y^(1p) to thereby produce a compoundof a general formula (I-3):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X⁹, X², X³, R¹and R² in formula (Ig); and Y is a group derived from Y^(1p) in formula(Ig) by removing or converting the protective group for the functionalgroup of Y^(1p)] (claim 15).

BEST MODE FOR CARRYING OUT THE INVENTION

Unless otherwise specifically indicated, the group as referred to inthis description concretely includes those mentioned below.

“Halogen atom” includes, for example, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom.

“Lower alkyl group” may be a linear or branched C1 to C6 alkyl group,including, for example, a methyl group, an ethyl group, a propyl group,an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group,a tert-butyl group, a pentyl group, an isoamyl group, a neopentyl group,an isopentyl group, a 1,1-ethylpropyl group, a 1-methylbutyl group, a2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, anisohexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a3-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutylgroup, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethylbutylgroup, a 2-ethylbutyl group, a 1,2,2-trimethylpropyl group, a1-ethyl-2-methylpropyl group.

“Lower alkoxy group” means a hydroxyl group of which the hydrogen atomis substituted with the above-mentioned lower alkyl group, including,for example, a methoxy group, an ethoxy group, a propoxy group, anisopropoxy group, a butoxy group, a sec-butoxy group, a tert-butoxygroup, a pentyloxy group, an isopentyloxy group, a hexyloxy group, anisohexyloxy group.

“Mono-lower alkylcarbonyloxy group” means a carbonyloxy group to beformed by substitution of the hydrogen atom of a formyloxy group withthe above-mentioned lower alkyl group, including, for example, amethylcarbonyloxy group, an ethylcarbonyloxy group, a propylcarbonyloxygroup, an isopropylcarbonyloxy group.

“Alkanoyl group” may be a lower alkanoyl group, including, for example,a formyl group, an acetyl group, a propionyl group, a butyryl group, apivaloyl group.

“C3 to C9 cycloalkyl group” includes, for example, a cyclopropyl group,a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, acycloheptyl group, a cyclooctyl group, a cyclononyl group.

“Aryl group” includes, for example, a phenyl group, a 1-naphthyl group,a 2-naphthyl group.

“Aralkyl group” may be the above-mentioned lower alkyl group having theabove-mentioned aryl group, including, for example, a benzyl group, a1-phenylethyl group, a 2-phenylethyl group, a 1-naphthylmethyl group, a2-naphthylmethyl group.

“Heteroaryl group” means a 5- or 6-membered monocyclic heteroaryl grouphaving therein from 1 to 3 hetero atoms selected from an oxygen atom, asulfur atom and a nitrogen atom, including, for example, a 5-memberedcyclic group such as a 2-furyl group, a 3-furyl group, a 2-thienylgroup, a 3-thienyl group, a 1-pyrrolyl group, a 2-pyrrolyl group, a3-pyrrolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a4-imidazolyl group, a 1-pyrazolyl group, a 3-pyrazolyl group, a4-pyrazolyl group, a 1-(1,2,4-triazolyl) group, a 3-(1,2,4-triazolyl)group, a 1-(1,2,3-triazolyl) group, a 4-(1,2,3-triazolyl) group, a2-thiazolyl group, a 4-thiazolyl group, a 5-thiazolyl group, a4-(1,2,3-thiadiazolyl) group, a 3-(1,2,4-thiadiazolyl) group, a2-(1,3,4-thiadiazolyl) group, a 3-isothiazolyl group, a 4 isothiazolylgroup, a 2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, a3-isoxazolyl group, a 4 isoxazolyl group; and a 6-membered cyclic groupsuch as a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a2-pyrimidinyl group, a 4-pyrimidinyl group, a 5-pyrimidinyl group, a3-pyridazinyl group, a 4-pyridazinyl group, a 5-pyridazinyl group, a2-pyrazinyl group.

“Heterocyclic group” may be a 3-membered to 8-membered monocyclicheterocyclic group containing from 1 to 3 hetero atoms selected from anoxygen atom, a sulfur atom and a nitrogen atom, including, for example,a 1-aziridinyl group, a 1-azetidinyl group, a 2-azetidinyl group, a1-pyrrolidinyl group, a 2-pyrrolidinyl group, a 3-pyrrolidinyl group, a1-piperidino group, a 2-piperidyl group, a 3-piperidyl group, a4-piperidyl group, a 1-hexamethyleneiminyl group, a2-hexamethyleneiminyl group, a 3-hexamethyleneiminyl group, a4-hexamethyleneiminyl group, a 1-heptamethyleneiminyl group, a2-heptamethyleneiminyl group, a 3-heptamethyleneiminyl group, a4-heptamethyleneiminyl group, a 1-pyrazolidinyl group, a 3-pyrazolidinylgroup, a 4 pyrazolidinyl group, a 1-piperazinyl group, a 2-piperazinylgroup, a 1-homopiperazinyl group, a 2-homopiperazinyl group, a5-homopiperazinyl group, a 6-homopiperazinyl group, a 2-oxetanyl group,a 3-oxetanyl group, a 2-tetrahydropyranyl group, a 3-tetrahydrofuranylgroup, a 2-tetrahydropyranyl group, a 3-tetrahydropyranyl group, a4-tetrahydropyranyl group, a 2-tetrahydrothiophenyl group, a3-tetrahydrothiophenyl group, a 2-thianyl group, a 3-thianyl group, a4-thianyl group, a 2-morpholinyl group, a 3-morpholinyl group, amorpholino group, a 2-thiazolidinyl group, a 3-thiazolidino group, a4-thiazolidinyl group, a 5-thiazolidinyl group.

“Cycloalkyliminocarbamoyl group” means a carbamoyl group substitutedwith a cycloalkylamino group. The cycloalkylamino group means a groupderived from the above-defined cycloalkyl group by substituting one CH₂constituting the cycloalkyl group with NH. The cycloalkyliminocarbamoylgroup includes, for example, an azetidin-2-yl-carbamoyl group, anazetidin-3-yl-carbamoyl group, a pyrrolidin-2-yl-aroyl group, apyrrolidin-3-yl-carbamoyl group, a piperidin-2-yl-carbamoyl group, apiperidin-3-yl-carbamoyl group, a piperidin-4-yl-carbamoyl group, ahexamethyleneimine-2-yl-carbamoyl group, ahexamethyleneimine-3-yl-carbamoyl group, ahexamethyleneimine-4-yl-carbamoyl group, aheptamethyleneimine-2-yl-carbamoyl group, aheptamethyleneimine-3-yl-carbamoyl group, aheptamethyleneimine-4-yl-carbamoyl group, aheptamethyleneimine-5-yl-carbamoyl group.

“Mono-lower alkylcarbamoyl group” means a carbamoyl group substitutedwith one above-mentioned lower alkyl group, including, for example, amethylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group,an isopropylcarbamoyl group, a butylcarbamoyl group, asec-butylcarbamoyl group, a tert-butylcarbamoyl group.

“Di-lower alkylcarbamoyl group” means a carbamoyl group substituted withtwo above-mentioned lower alkyl groups that may be the same ordifferent, including, for example, a dimethylcarbamoyl group, adiethylcarbamoyl group, an ethylmethylcarbamoyl group, adipropylcarbamoyl group, a methylpropylcarbamoyl group, adiisopropylcarbamoyl group.

The di-lower alkylcarbamoyl group further includes a 5-membered to8-membered monocyclic or spin cyclic group to be formed by the nitrogenatom constituting the carbamoyl group and the same or different loweralkyl groups bonding to the nitrogen atom, and a bicyclic group to beformed through condensation of the 5-membered to 8-membered monocyclicgroup with a benzene or pyridine ring. Concretely, these are groups ofthe following formula (b):

“Lactam ring” includes a 3-membered to 9-membered monocyclic grouphaving a group of —N(R⁶)—C(O)— in the ring, or a group having 1 or 2carbon-carbon double bonds in the ring, or a group having 1 or 2 oxygenatoms or nitrogen atoms in addition to the nitrogen atom thatconstitutes —N—C(O)—. Not specifically defined, the bonding position ofthe lactam ring may be any one to which the ring may bond. R⁶ representsa hydrogen atom or a lower alkyl group. More concretely, the lactam ringincludes those of the following formula (c):

Of those, preferred are β-propiolactam, 2-pyrrolidone-1-yl,2-piperidon-1-yl, 2-piperidon-1-yl, 2-morpholidon-1-yl.

“Mono-lower alkylamino group” means an amino group substituted with oneabove-mentioned lower alkyl group, including, for example, a methylaminogroup, an ethylamino group, a propylamino group, an isopropylaminogroup, a butylamino group, a sec-butylamino group, a tert-butylaminogroup.

“Di-lower alkylamino group” means an amino group substituted twoabove-mentioned lower alkyl groups, including, for example, adimethylamino group, a diethylamino group, a dipropylamino group, adiisopropylamino group, a methylethylamino group, a methylpropylaminogroup.

“Mono-lower alkylaminocarbonyloxy group” means a carbonyloxy group to beformed by substituting the hydrogen atom of a formyloxy group with anammo group substituted with one above-mentioned lower alkyl group,including, for example, a methylaminocarbonyloxy group, anethylaminocarbonyloxy group, a propylaminocarbonyloxy group, anisopropylaminocarbonyloxy group.

“Di-lower alkylcarbamoyloxy group” means a carbamoyloxy groupsubstituted with two above-mentioned lower alkyl groups that may be thesame or different, including, for example, a dimethylcarbamoyloxy group,a diethylcarbamoyloxy group, a diisopropylcarbamoyloxy group, anethylmethylcarbamoyloxy group.

“Alkylene group” means a C1 to C6 linear or branched alkylene group,including, for example, a methylene group, an ethylene group, atrimethylene group, a tetramethylene group, a pentamethylene group.

The novel piperidine derivatives of the invention are represented by thefollowing general formula (I):

in which a predetermined nitrogen-containing heterocyclic group bonds tothe 4-position of the piperidine ring and a predetermined aromatic ringbonds to the 1-position of the piperidine ring. Not specificallydefined, the novel piperidine derivatives of the invention includesthose as above and their pharmaceutically-acceptable salts.

In formula (I), X³ in the nitrogen-containing heterocyclic group thatbonds to the 4-position of the piperidine ring indicatesO_(s)—(CH₂)_(m); s indicates 0 or 1; m indicates an integer to make(m+s) 0 or from 1 to 4. The nitrogen-containing heterocyclic group maybe a 4-membered to 8-membered group, concretely including a 1-azetidinylgroup, a 1-pyrrolidinyl group, a piperidino group, a1-hexamethyleneiminyl group, a 1-heptamethyleneiminyl group, amorpholino group. Of those, preferred are a 1-pyrrolidinyl group, apiperidino group, a 1-hexamethyleneiminyl group; and more preferred is apiperidino group.

R¹ and R² in the nitrogen-containing heterocyclic group areindependently a hydrogen atom, a halogen atom, a linear or branchedlower alkyl group, a lower alkoxy group, or an acetyl group substitutedwith 2 or 3 fluorine atoms. The halogen atom, the linear or branchedlower alkyl group and the lower alkoxy group for R¹ and R² areconcretely those mentioned hereinabove. The acetyl group substitutedwith 2 or 3 fluorine atoms for R¹ and R² includes, for example, aperfluoroacetyl group, a difluoroacetyl group. Of those substituents, R¹and R² are preferably hydrogen atoms.

In formula (I), X¹ and X² in the aromatic ring bonding to the 1-positionof the piperidin ring independently represent a nitrogen atom or CH. Asso mentioned hereinunder, their preferred combinations may be selecteddepending on the hydrogen atom or the substituent Y bonding to thearomatic ring.

In formula (I), the substituent Y of the aromatic ring bonding to the1-position of the piperidine ring is represented by the followinggeneral formula (II):

In formula (II), L₁ represents a C1 to C4 alkylene group or a singlebond, preferably a single bond, or a C1 to C3 alkylene group such as amethylene group, an ethylene group, a propylene group; more preferably asingle bond, a methylene group or an ethylene group.

In formula (II), M represents an oxygen atom or a group of the followinggeneral formula (III):

In formula (III), R⁰ represents a hydrogen atom or a C1 to C4 alkylgroup. The C1 to C4 alkyl group for R⁰ includes, for example, a methylgroup, an ethyl group, a propyl group, an n-butyl group, an isopropylgroup, an isobutyl group, a tert-butyl group. Of those, preferred are amethyl group, an ethyl group, a propyl group, an n-butyl group, anisopropyl group; and more preferred are a methyl group, an ethyl group,a propyl group, an isopropyl group.

In formula (II), j, k and l independently indicate 0 or 1. A grouprepresented by Y in formula (II) includes, for example, the following:

-Q₁, —(CH₂)_(n)-Q₁ (n indicates an integer of from 1 to 4, and the sameshall apply hereinunder), —O-Q₁, —(NR⁰)-Q₁, —(CH₂)_(n)—(NR⁰)-Q₁,—(CO)-Q₁, —(CO)—(CH₂)_(n)-Q₁, —(CO)—O-Q₁, —(CO)—(NR⁰)-Q₁,—(CO)—(CH₂)_(n)-Q₁, —(CO)—(CH₂)_(n)—(NR⁰)-Q₁, —O—(CH₂)_(n)-Q₁, —O—O-Q₁,—O—(NR⁰)-Q₁, —O—(CH₂)_(n)—O-Q₁, —O—(CH₂)_(n)—(NR⁰)-Q₁,—O—(CO)—(CH₂)_(n)-Q₁, —O—(CO)—O-Q₁, —O—(CO)—(NR⁰)-Q₁,—O—(CO)—(CH₂)_(n)—O-Q₁, —O—(CO)—(CH₂)_(n)—(NR⁰)-Q₁.

Of those, preferred are —(CH₂)_(n)-Q₁, —(CO)-Q₁, —(CO)-Q₁,—(CH₂)_(n)—(CO)-Q₁, —(CH₂)_(n)—(CO)—O-Q₁, —(CO)—(NR⁰)-Q₁,—(CH₂)_(n)—(CO)—(NR⁰)-Q₁, —O—(CH₂)_(n)-Q₁; more preferred are—(CH₂)_(n)-Q₁, —(CO)—O-Q₁, —(CH₂)_(n)—(CO)—O-Q₁, —(CO)—(NR⁰)-Q₁,—(CH₂)—(CO)—(NR⁰)-Q₁, —O-Q₁, —O—(CH₂)_(n)-Q₁.

In formula (II), Q₁ represents a linear or branched lower alkyl group,an optionally-condensed C3 to C9 cycloalkyl group, a phenyl group, anaphthyl group, or an optionally-condensed 3-membered to 8-memberedheterocyclic group. These groups may be unsubstituted, or may besubstituted with one or more substituents selected from a cyano group, ahydroxyl group, a lower alkyl group (the lower alkyl group may befurther substituted with a hydroxyl group, a halogen atom, an aminogroup, an aryl group or a heteroaryl group), a cycloalkyl group, a loweralkoxy group (the lower alkoxy group may be further substituted with ahalogen atom), a halogen atom, a mono-lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyl group, acycloalkyliminocarbamoyl group, a lactam ring, a trifluoromethyl group,a mono-lower alkylamino group, a di-lower alkylamino group and analkanoyl group.

The linear or branched lower alkyl group represented by Q₁ may be alinear or branched C1 to C6 alkyl group, concretely including thosementioned hereinabove. Of those, preferred are a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, a pentyl group, an isoamylgroup, a neopentyl group, an isopentyl group, a 1,1-dimethylpropylgroup, a 1-methylbutyl group, a 2-methylbutyl group, a1,2-dimethylpropyl group, an n-hexyl group, an isohexyl group; and morepreferred are a methyl group, an ethyl group, a propyl group, anisopropyl group, a butyl group, an isobutyl group, a sec-butyl group, atert-butyl group, a pentyl group, an isoamyl group, a neopentyl group,an isopentyl group, a 1,1-dimethylpropyl group, a hexyl group, anisohexyl group.

Of the substituents mentioned hereinabove, the substituent that thelinear or branched lower alkyl group for Q₁ may have is more preferablya cyano group, a hydroxyl group, a lower alkoxy group (the lower alkoxygroup may be further substituted with a halogen atom), a halogen atom,an amino group, an aryl group, a heteroaryl group, a di-loweralkylaminocarbonyloxy group, a di-lower alkylcarbamoyl group and atrifluoromethyl group, even more preferably a hydroxyl group, a loweralkoxy group (the lower alkoxy group may be further substituted with ahalogen atom) and a trifluoromethyl group.

The lower alkoxy group for the substituent in the linear or branchedlower alkyl group for Q₁ concretely includes those mentionedhereinabove. The lower alkoxy group may be further substituted with ahalogen atom. The halogen atom concretely includes those mentionedhereinabove. The di-lower alkylcarbamoyl group, the di-loweralkylaminocarbonyloxy group, the aryl group and the heteroaryl group forthe substituent in the linear or branched lower alkyl group for Q₁concretely includes those mentioned hereinabove. The linear or branchedlower alkyl group for Q₁ may have 1 or 2 above-mentioned substituents attheir bondable positions.

In formula (II), the C3 to C9 cycloalkyl group for Q₁ concretelyincludes those mentioned hereinabove. Of those, preferred are acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group; more preferred are a cyclopropyl group, acyclobutyl group, a cyclopentyl group, a cyclohexyl group. The C3 to C9cycloalkyl group for Q₁ may be a bicyclic group condensed with a benzenering, for example, a 1-benzo[b]cyclopropyl group, a 1-benzo[b]cyclobutylgroup, a 1-benzo[b]cyclopentyl group, a 1-benzo[b]cyclohexyl group, a1-benzo[c]heptyl group, a 1-benzo[c]cyclooctyl group, a1-benzo[c]cyclononyl group.

The substituent that the C3 to C9 cycloalkyl group for Q₁ may have ispreferably a cyano group, a hydroxyl group, a lower alkyl group (thelower alkyl group may be further substituted with a hydroxyl group, ahalogen atom, an amino group, an aryl group, a heteroaryl group), alower alkoxy group (the lower alkoxy group may be further substitutedwith a halogen atom), a halogen atom, a mono-lower alkylcarbonyloxygroup, a di-lower alkylcarbamoyloxy group, a mono-lower alkylcarbamoylgroup, a di-lower alkylcarbamoyl group, a carbamoyl group, acycloalkyliminocarbamoyl group, a lactam ring, a trifluoromethyl group,a mono-lower alkylamino group, a di-lower alkylamino group and analkanoyl group. Of those, more preferred are a hydroxyl group, a loweralkyl group (the lower alkyl group may be further substituted with ahydroxyl group, a halogen atom or an amino group), a lower alkoxy group(the lower alkoxy group may be further substituted with a halogen atom),a halogen atom, a mono-lower alkylcarbonyloxy group, a di-loweralkylcarbamoyloxy group, a mono-lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a cycloalkyliminocarbamoyl group, a lactam ring, amono-lower alkylamino group, a di-lower alkylamino group and an alkanoylgroup. “Lower alkyl group”, “lower alkoxy group”, “halogen atom”,“mono-lower alkylcarbonyloxy group”, “di-lower alkylcarbamoyloxy group”,“mono-lower alkylcarbamoyl group”, “di-lower alkylcarbamoyl group”,“cycloalkyliminocarbamoyl group”, “lactam ring”, “mono-lower alkylaminogroup”, and “di-lower alkylamino group” for the substituent of the C3 toC9 cycloalkyl group for Q¹ are concretely the same as those mentionedhereinabove. The C3 to C9 cycloalkyl group for Q¹ may have 1 or 2 thesesubstituents at their bondable positions.

Of the substituents mentioned hereinabove, the substituent that thephenyl group for Q¹ in formula (II) may have is preferably a cyanogroup, a hydroxyl group, a lower alkyl group (the lower alkyl group maybe further substituted with a hydroxyl group, a halogen atom or an aminogroup), a lower alkoxy group (the lower alkoxy group may be furthersubstituted with a halogen atom), a halogen atom, a mono-loweralkylcarbonyloxy group, a di-lower alkylcarbamoyloxy group, a mono-loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoylgroup, a lactam ring, a trifluoromethyl group, a mono-lower alkylaminogroup, a di-lower alkylamino group and an alkanoyl group. Of those, morepreferred are a hydroxyl group, a lower alkyl group (the lower alkylgroup may be further substituted with a hydroxyl group, a halogen atomor an amino group), a lower alkoxy group (the lower alkoxy group may befurther substituted with a halogen atom), a halogen atom, a mono-loweralkylcarbonyloxy group, a di-lower alkylcarbamoyloxy group, a mono-loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, acycloalkyliminocarbamoyl group, a lactam ring, a mono-lower alkylaminogroup, a di-lower alkylamino group and an alkanoyl group. “Lower alkylgroup”, “lower alkoxy group”, “halogen atom”, “mono-loweralkylcarbonyloxy group”, “di-lower alkylcarbamoyloxy group”, “mono-loweralkylcarbamoyl group”, “di-lower alkylcarbamoyl group”,“cycloalkyliminocarbamoyl group”, “lactam ring”, “mono-lower alkylaminogroup”, and “di-lower alkylamino group” for the substituent of thephenyl group for Q¹ are concretely the same as those mentionedhereinabove. The phenyl group for Q¹ may have 1 or 2 these substituentsat their bondable positions.

Of the substituents mentioned hereinabove, the substituent that thenaphthyl group for Q¹ in formula (II) may have is preferably a cyanogroup, a hydroxyl group, a lower alkyl group (the lower alkyl group maybe further substituted with a hydroxyl group, a halogen atom or an aminogroup), a lower alkoxy group (the lower alkoxy group may be furthersubstituted with a halogen atom), a halogen atom, a mono-loweralkylcarbonyloxy group, a di-lower alkylcarbamoyloxy group, a mono-loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoylgroup, a lactam ring, a trifluoromethyl group, a mono-lower alkylaminogroup, a di-lower alkylamino group and an alkanoyl group. Of those, morepreferred are a hydroxyl group, a lower alkyl group (the lower alkylgroup may be further substituted with a hydroxyl group, a halogen atomor an amino group), a lower alkoxy group (the lower alkoxy group may befurther substituted with a halogen atom), a halogen atom, a mono-loweralkylcarbonyloxy group, a di-lower alkylcarbamoyloxy group, a mono-loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, acycloalkyliminocarbamoyl group, a lactam ring, a mono-lower alkylaminogroup, a di-lower alkylamino group and an alkanoyl group. “Lower alkylgroup”, “lower alkoxy group”, “halogen atom”, “mono-loweralkylcarbonyloxy group”, “di-lower alkylcarbamoyloxy group”, “mono-loweralkylcarbamoyl group”, “di-lower alkylcarbamoyl group”, “lactam ring”,“mono-lower alkylamino group”, and “di-lower alkylamino group” for thesubstituent of the naphthyl group for Q¹ are concretely the same asthose mentioned hereinabove. The naphthyl group for Q¹ may have 1 or 2these substituents at their bondable positions.

In formula (II), the optionally-condensed 3-membered to 8-memberedheterocyclic group for Q¹ is a 3-membered to 8-membered cyclic compoundresidue containing from 1 to 3 hetero atoms selected from an oxygenatom, a sulfur atom and a nitrogen atom. The heterocyclic group includesa monocyclic group of a 5-membered or 6 membered heteroaryl group havingfrom 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom anda nitrogen atom; a bicyclic or tricyclic group formed throughcondensation of the monocyclic heteroaryl group with a benzene ring or apyridine ring; a monocyclic group of a 3-membered to 8-memberedheterocyclic group; and a bicyclic group formed through condensation ofthe monocyclic heterocyclic group with a benzene ring or a pyridinering. The 5-membered or 6-membered heteroaryl group includes the same asthose mentioned hereinabove. Of those, preferred are a furyl group, athienyl group, a pyrrolyl group, a pyrazolyl group, a thiazolyl group, athiadiazolyl group, an isothiazolyl group, an oxazolyl group, anisoxazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinylgroup; and more preferred are a pyrazolyl group, a thiazolyl group, athiadiazolyl group, an isothiazolyl group, an oxazolyl group, anisoxazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinylgroup.

The bicyclic or tricyclic group to be formed through condensation of amonocyclic heteroaryl group and a benzene ring or a pyridine ring for Q¹includes, for example, a bicyclic group such as a 2-benzofuranyl group,a 3-benzofuranyl group, a 1-indolyl group, a 2-indolyl group, a3-indolyl group, a 2-quinolyl group, a 4-quinolyl group, a 8-quinolylgroup, a 1-isoquinolyl group, a 3-isoquinolyl group, a 4-isoquinolylgroup, a 2-benzoxazolyl group, a 3-benzoxazolyl group, a1-benzimidazolyl group, a 2-benzimidazolyl group, a 1-phthalazinylgroup, a 2-phthalazinyl group, a quinoxalinyl group, a 2-quinazolinylgroup, a 4-quinazolinyl group a 4-(4H-quinolidinyl) group, a3-cinnolinyl group, a 4-cinnolinyl group, a 1-pyridoimidazolyl group, a2-imidazopyridyl group, a 2-(1,5-naphthyridinyl) group, a2-(1,8-naphthyridinyl) group, a 2-(2,7-naphthyridinyl) group, a2-benzisoxazolyl group, a benzothiazolyl group, a pyridooxazolyl group,a pyridothiazolyl group, a pyridoisothiazolyl group, a benzothienylgroup; and a tricyclic group such as a 2-benzo[g]quinolyl group, a2-pyrido[g]quinolyl group, a 2-benzo[g]quinazolinyl group, a2-pyrido[g]quinazolinyl group, a 3-benzo[g]-cinnolyl group, a3-pyrido[g]cinnolyl group, a 2-benzo[g]quinoxaloyl group, a2-pyrido[g]quinoxaloyl group. Of those, preferred are a benzofuranylgroup, an indolyl group, a quinolinyl group, an isoquinolinyl group, abenzoxazolyl group, a benzimidazolyl group, a phthalazinyl group, anaphthyridinyl group, an quinoxalinyl group, a quinazolinyl group, acinnolinyl group, an imidazopyridinyl group; and more preferred are aquinolinyl group, an isoquinolinyl group, a benzoxazolyl group, abenzimidazolyl group, a phthalazinyl group, a naphthyridinyl group, aquinoxalinyl group, a quinazolinyl group, a cinnolinyl group, animidazopyridinyl group.

The 3-membered to 8-membered heterocyclic group for Q¹ may be the sameas those mentioned hereinabove. Of those, preferred are an oxetanylgroup, a tetrahydrofuranyl group, a tetrahydropyranyl group, apyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, amorpholinyl group, a homomorpholinyl group; and more preferred are anoxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, apiperidinyl group, a homopiperidinyl group.

The bicyclic group formed through condensation of a monocyclic3-membered to 8-membered heterocyclic group and a benzene ring or apyridine ring for Q¹ includes, for example, a 1-benzo[b]azetidinylgroup, a 2-benzo[c]azetidinyl group a 1-benzo[b]pyrrolidinyl group, a2-benzo[d]pyrrolidinyl group, a 3-benzo[d]pyrrolidinyl group, a1-benzo[b]piperidino group, a 2-benzo[e]piperidyl group, a3-benzo[e]piperidyl group, a 4-benzo[b]piperidyl group, a1-benzo[c]hexamethyleneiminyl group, a 2-benzo[d]hexamethyleneiminylgroup, a 3-benzo[e]hexamethyleneiminyl group, a4-benzo[f]hexamethyleneiminyl group, a 1-benzo[e]heptamethyleneiminylgroup, a 2-benzo[e]heptamethyleneiminyl group, a3-benzo[c]heptamethyleneiminyl group, a 4-benzo[c]heptamethyleneiminylgroup, a 1-benzo[d]pyrazolidinyl group, a 3-benzo[d]pyrazolidinyl group,a 4-benzo[d]pyrazolidinyl group, a 1-benzo[b]piperazinyl group, a2-benzo[b]piperazinyl group, a 1-benzo[b]homopiperazinyl group, a2-benzo[e]homopiperazinyl group, a 5-benzo[f]homopiperazinyl group, a6-benzo[b]homopiperazinyl group, a 2-pyrido[b]tetrahydrofuranyl group, a3-pyrido[b]tetrahydrofuranyl group, 2-pyrido[b]tetrahydropyranyl group,3-pyrido[d]tetrahydropyranyl group, a 4-pyrido[b]tetrahydropyranylgroup, a 2-pyrido[e]morpholinyl group, a 3-pyrido[e]morpholinyl group, apyrido[b]morpholino group, a 2-benzo[d]thiazolidinyl group, a3-benzo[d]thiazolidino group.

Of the substituents mentioned hereinabove, the substituent that theoptionally-condensed 3-membered to 8-membered heterocyclic group for Q¹may have is preferably a cyano group, a hydroxyl group, a lower alkylgroup (the lower alkyl group may be further substituted with a hydroxylgroup, a halogen atom or an amino group), a lower alkoxy group (thelower alkoxy group may be further substituted with a halogen atom), ahalogen atom, a mono-lower alkylcarbonyloxy group, a di-loweralkylcarbamoyloxy group, a mono-lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyl group, a lactam ring, atrifluoromethyl group, a mono-lower alkylamino group, a di-loweralkylamino group and an alkanoyl group, more preferably a hydroxylgroup, a lower alkyl group (the lower alkyl group may be furthersubstituted with a hydroxyl group, a halogen atom or an amino group), alower alkoxy group (the lower alkoxy group may be further substitutedwith a halogen atom), a halogen atom, a mono-lower alkylcarbonyloxygroup, a di-lower alkylcarbamoyloxy group, a mono-lower alkylcarbamoylgroup, a di-lower alkylcarbamoyl group, a cycloalkyliminocarbamoylgroup, a lactam ring, a mono-lower alkylamino group, a di-loweralkylamino group and an alkanoyl group. “Lower alkyl group”, “loweralkoxy group”, “halogen atom”, “mono-lower alkylcarbonyloxy group”,“di-lower alkylcarbamoyloxy group”, “mono-lower alkylcarbamoyl group”,“di-lower alkylcarbamoyl group”, “lactam ring”, “mono-lower alkylaminogroup”, and “di-lower alkylamino group” in the 3-membered to 8-memberedheterocyclic group for Q¹ are concretely the same as those mentionedhereinabove. The 3-membered to 8-membered heterocyclic group and thebicyclic or tricyclic group formed through condensation of theheterocyclic group with a benzene or pyridine ring for Q¹ may have 1 or2 these substituents at their bondable positions.

Y in formula (II) is preferably the following (1) and (2):

Case (1):

Y in formula (II) is preferably a group of the following general formula(V):

Y of formula (V) preferably includes the following 4 embodiments.

The first embodiment is as follows: In formula (IV), R³ represents ahydrogen atom or a lower alkyl group, and R⁴ represents a group of thefollowing general formula (V):

(wherein R⁵ represents a hydrogen atom, a lower alkyl group, a C3 to C8cycloalkyl group, an aralkyl group or a heteroaryl group; n indicates 0or an integer of from 1 to 4). In formula (IV), the alkyl group for R³concretely includes a methyl group, an ethyl group. The group for R³ ispreferably a methyl group, a hydrogen atom or an ethyl group in thatorder. The lower alkyl group for R⁵ in formula (V) that represents R⁴includes a methyl group, an ethyl group. The aralkyl group concretelyincludes the same as those mentioned hereinabove. The C3 to C8cycloalkyl group may be the same as those mentioned hereinabove for theabove-mentioned C3 to C9 cycloalkyl group, but excepting a cyclononylgroup. The heteroaryl group may be a 5-membered or 6-membered monocyclicheteroaryl group having a hetero atom selected from the group consistingof an oxygen atom, a sulfur atom and a nitrogen atom, and it may includethe same as those mentioned hereinabove for the above-mentionedheteroaryl group.

The second embodiment is as follows: In formula (IV), R³ represents ahydrogen atom or a lower alkyl group, R⁴ represents a group of thefollowing general formula (V):

—(CH₂)_(q)-A  (VI)

(wherein A represents an aryl group, a heteroaryl group, a condensedbicyclic group of a C4 to C7 cycloalkyl group and an aryl group, or acondensed bicyclic group of a C4 to C7 cycloalkyl group and a heteroarylgroup; q indicates 0 or an integer of from 1 to 3). In formula (IV), thelower alkyl group for R³ concretely includes a methyl group, an ethylgroup. The aryl group and the heteroaryl group for A in formula (VI)that represents R³ concretely includes the same as those mentionedhereinabove. The C4 to C7 cycloalkyl group concretely includes acyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptylgroup.

The third embodiment is as follows: In formula (IV), R³ and R⁴ form anitrogen containing heterocyclic group along with the nitrogen atombonding to them. The nitrogen-containing heterocyclic group may be amonocyclic group, including, for example, a piperidinyl group, apyrrolidinyl group, an azetidinyl group, a homopiperidinyl group, aheptamethyleneiminyl group.

The fourth embodiment is as follows: The nitrogen-containingheterocyclic group in the third embodiment is condensed with a phenylgroup or a pyridyl group to form a bicyclic group. The bicyclic groupmay include the same as those mentioned hereinabove for theabove-mentioned heterocyclic group.

When Y in formula (II) indicates any of the above-mentioned for 4embodiments, then the aromatic ring in formula (I) to which Y bonds ispreferably a phenyl group where X¹ and X² are both CH; or a pyridylgroup where any of them is a nitrogen atom

Case (2):

Y in formula (II) is preferably an aryl group or a 5-membered or6-membered heteroaryl group, which is unsubstituted or has, in the ringthereof, 1 or 2 substituents selected from a group consisting of a loweralkyl group, a lower alkoxy group, a hydroxyl group and a halogen atom,and may have, in the ring thereof, from 1 to 3 hetero atoms selectedfrom a group consisting of a nitrogen atom, a sir atom and an oxygenatom. The aryl group or the 5-membered or 6-membered heteroaryl groupmay include the same as those mentioned hereinabove for the aryl groupor the 5-membered or 6-membered heteroaryl group for R⁵ in formula (V)or for A in formula (VI). The substituent in the ring of the aryl groupor the 5-membered or 6-membered heteroaryl group includes, for example,a lower alkyl group such as a methyl group, an ethyl group; a loweralkoxy group such as a methoxy group, an ethoxy group; a halogen atomsuch as a fluorine atom, a chlorine atom, an iodine atom; and a hydroxylgroup. When Y in formula (II) is an aryl group or a heteroaryl groupthat is unsubstituted or has the above-mentioned substituent, then thearomatic ring which bonds to the 1-position of the piperidine ring informula (I) and to which Y bonds is preferably a pyrimidine ring whereX¹ and X² are both nitrogen atoms.

Concretely, the piperidine derivatives of formula (I) include compoundslisted in Table 1 to Table 5.

TABLE 1

Heterocyclic Group Bonding to Piperidine X¹ X² Ring R¹ R² CH CH

H H N N

F F

—CH₃

—COCH₃

—OCF₃

Y —CH₃ —C₂H₅ —C₃H₇ —C₄H₉ —C(CH₃)C₂H₅ —C₅H₁₁ —CH₂CH(CH₃)C₂H₅ —C(CH₃)HC₃H₇—C₆H₁₃

Substituent for Y —CN —OH —OCH₃ —OC₂H₅ —OCH₂Cl —OCH₂F —OC₂H₄Cl —OC₂H₄F—NH₂ —F —Cl —CONH(CH₃) —CONH(C₂H₅) —OCON(CF₃)₂ —OCON(C₂H₅)₂—OCON(C₂H₅)(CH₃) —CF₃

—CN —OH —CH₃ —C₂H₅ —CH₂Cl —CH₂OH —CH₂(NH₂)

—F —Cl —OCOCH₃ —OCOCH₂F —OCOCH₂Cl —OCOC₂H₄F —OCOC₂H₄Cl —CONH₂ —CONH(CH₃)—CONH(C₂H₅) —CON(C₃H₇)₂ —CON(C₃H₇)(CH₃)

—NH(CH₃) —NH(C₂H₅) —NH(C₃H₇) —NH(CH(CH₃)₂) —NH(C(CH₃)₃) —N(CH₃)₂—N(C₂H₅)₂ —N(C₃H₇)₂ —N(CH(CH₃)₂)₂ —CF₃

TABLE 2

Heterocyclic Group Bonding to Piperidine X¹ X² Ring R¹ R² CH CH N

H F —CH₃ —COCH₃ —OCF₃ H F

Q₁

—CH₃ —C₂H₅ —C₃H₇ —C₄H₉ (n = 1~3) —C(CH₃)C₂H₅ —C₅H₁₁ —O— —CH₂CH(CH₃)C₂H₅—C(CH₃)HC₃H₇

—C₆H₁₃

Substituent for Q1 —CN —OH —OCH₃ —OC₂H₅ —OCH₂ Cl —OCH₂F —OC₂H₄ Cl—OC₂H₄F —NH₂ —F —Cl —CONH(CH₃) —CONH(C₂H₅) —OCON(CF₃)₂ —OCON(C₂H₅)₂—OCON(C₂H₅)(CH₃) —CF₃

—CN —OH —CH₃ —C₂H₆ —CH₂Cl —CH₂OH —CH₂(NH₂)

—F —Cl —OCOCH₃ —OCOCH₂F —OCOCH₂Cl —OCOC₂H₄F —OCOC₂H₄Cl —CONH₂ —CONH(CH₃)—CONH(C₂H₅) —CON(C₃H₇)₂ —CON(C₃H₇)(CH₃)

—NH(CH₃) —NH(C₂H₅) —NH(CH(CH₃)₂) —NH(C(CH₃)₃) —N(CH₃)₂ —N(C₂H₅)₂—N(C₃H₇)₂ —N(CH(CH₃)₂)₂ —CF₃

TABLE 3

X¹ X² X³ R¹ R² R³ R⁴ R⁵ CH CH

H H —CH₃

—CH₃ —C₂H₅ —C₃H₇ —C₄H₉ —C(CH₃)C₂H₅ N F F —H

—C₅H₁₁ —CH₂(CH₃)C₂H₅ —C(CH₃)HC₃H₇ —CH₃ —C₂H₅

—C₆H₁₃

—COCH₃

—OCF₃

X¹ X² X³ R¹ R² R³ R⁴ A CH CH

H H —CH₃ H

N F F —H

—CH₃ —C₂H₅

—COCH₃

—OCF₃

TABLE 4

X¹ X² X³ R¹ R²

CH N CH

H F —CH₃ —COCH₃ —OCF₃ H F

TABLE 5

X¹ X² X³ R¹ R² Y N N

H F —CH₃ —COCH₃ —OCF₃ H F

Substituent for Y —CH₃ —C₂H₅ —C₃H₇ —C₄H₉ —C(CH₃)C₂H₅ —C₅H₁₁—CH₂CH(CH₃)C₂H₅ —C(CH₃)HC₃H₇ —C₆H₁₃ CH₃CO— C₂H₅CO— OH Cl F

Of those piperidine derivatives, preferred are the following:

-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-ylpiperidin-1-yl]benzamide    (1),-   N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (2),-   N-methyl-N-(1-cyclobutylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (3),-   N-methyl-N-(1-cyclopentylpiperidine-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (4),-   N-methyl-N-(1-cyclohexylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (5),-   N-methyl-N-(1-cyclohexylmethylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (6),-   N-methyl-N-[(3R)-1-cyclopentylpyrrolidin-3-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (7),-   N-methyl-N-[(3S)-1-cyclopentylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (8),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (9),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (10),-   N-(pyridin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide (11),-   2-{4-(4-piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroisoquinoline    (12),-   1-{4-(4-piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroquinoline    (13),-   1-{4-(4-piperidin-1-yl)piperidin-1-yl]benzoyl-4-phenylpiperazine    (14),-   N-methyl-N-[1-(pyrimidin-2-yl)piperidin-4-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (15),-   N-methyl-N-(thiophen-2-yl)methyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (16),-   N-methyl-N-phenethyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (17),-   1-{4-(4-piperidin-1-yl)piperidin-1-yl]benzoyl-3-(3,4-difluorophenyl)pyrrolidine    (18),-   1-{4-(4-piperidin-1-yl)piperidin-1-yl]benzylpiperidin (19),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]benzamide    (20).

Also preferably, the piperidine derivatives of the invention are thefollowing:

-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4(azetidin-1-yl)piperidin-1-yl]benzamide    (21),-   N-methyl-N-(1-methylpiperidin-4-yl)-5-[4(piperidin-1-yl)piperidin-1-yl]pyridine-2-carboxamide    (22),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(4,4-difluoropiperidin-1-yl)piperidin-1-yl]benzamide    (23),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(4-cyanophenyl)-pyrimidine    (24),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(3-pyridyl)pyrimidine (25),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3-trifluoromethylphenyl)pyridine    (26),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3,5-dichlorophenyl)pyrimidine    (27),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(2-naphthyl)pyrimidine (28),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-[4-(pyrrolidin-1-ylcarbonyl)phenyl]pyrimidine    (29),-   1-[4(piperidin-1-yl)piperidin-1-yl]-4-(3-pyridyl)benzene (30),-   1-(piperidin-1-ylmethyl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzene    (31).

Not specifically defined, pharmaceutically-acceptable salts ofpiperidine derivatives of formula (I) are, for example, hydrohalidessuch as hydrofluorides, hydrobromides, hydroiodides; inorganic acidsalts such as nitrates, perchlorates, sulfates, phosphates, carbonates;lower alkylsulfonates such as methanesulfonates,trifluoromethanesulfonates, ethanesulfonates; arylsulfonates such asbenzesulfonates, p-toluenesulfonates; organic acid salts such asfumarates, succinates, citrates, tartrates, oxalates, maleates; andother acid-addition salts with organic acids such as amino acids, forexample, glutamates, aspartates. The salts may also be base-additionsalts, for example, salts with alkali metals such as sodium, potassium;salts with alkaline earth metals such as calcium, magnesium; ammoniumsalts; salts with organic bases such as guanidine, triethylamine,dicyclohexylamine. Further, the piperidine derivatives of formula (I) ofthe invention may be in the form of their esters, or hydrates orsolvates of their free compounds or pharmaceutically-acceptable salts oresters.

Methods for producing the piperidine derivatives of formula (I) of theinvention are described below. The piperidine derivatives of formula (I)may be produced, using any known reaction methods or according to anyper-se known methods. They may be produced not only according toordinary liquid-phase production methods but also according to anysolid-phase methods such as combinatorial production methods or parallelproduction methods that are being significantly developed these days.

Methods for producing the piperidine derivatives of formula (I) of theinvention are described below.

[Production Method 1]

A compound of a general formula (Ia):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (I); and L¹ represents a leaving group] is reactedwith a compound of a general formula (IIa):

Met-Y^(1p)  (IIa)

[wherein Met represents a metal atom-containing atomic group; and Y^(1p)has the same meaning as Y in a general formula (II):

or represents a group corresponding to it but protected at the aminogroup, the hydroxyl group or the carboxyl group therein], in thepresence of a catalyst to give a compound of a general formula (Ib):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (Ia); and Y^(1p) has the same meaning as Y^(1p) informula (IIa)], and optionally the protective group for the functionalgroup of Y^(1p) is removed or converted (e.g., for amine residueacylation, carboxylic acid residue amidation, alcohol residuealkylation) to thereby produce a compound of a general formula (I-1):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (Ib); and Y is a group derived from Y^(1p) in formula(Ib) by removing or converting the protective group for the functionalgroup of Y^(1p)].

The metal atom-containing atomic group for Met in formula (IIa) ispreferably an organic metal-containing atomic group generally used incross-coupling reaction. The metal atom to be in the metalatom-containing atomic group includes, for example, lithium, boron,silicon, magnesium, aluminium, zinc, tin, more preferably boron, zinc,tin. Regarding the concrete embodiments of the metal atom-containingatomic group, for example, boron is in the form of boric acid orborates; zinc is in the form of zinc chloride, zinc bromide or zinciodide; and tin is in the form of tri-lower alkyl-tin. Y^(1p) in formula(IIa) that contains a protective group for Y is described hereinunder.

The reaction of producing a compound of formula (Ib) from a compound offormula (Ia) and a compound of formula (IIa) is carried out, generallyusing from 0.5 mols to 5 mols, preferably from 0.7 mols to 3 mols of thecompound (IIa) relative to 1 mol of the compound (Ia). The catalyst forthe reaction is, for example, a transition metal generally used incross-coupling reaction, such as copper, nickel, palladium. Moreconcretely, preferred are tetrakis(triphenylphosphine)palladium(0),palladium(II) acetate, bis(triphenylphosphine)palladium(II) chloride,[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. Thereaction is effected generally in an inert solvent. The insert solventis, for example, preferably water, benzene, toluene, xylene, methylenechloride, chloroform, dimethoxyethane, tetrahydrofuran, dioxane,dimethylformamide, and their mixed solvents. The reaction temperaturemay be generally from room temperature to the boiling point of thesolvent used in the reaction, preferably from 20° C. to 200° C. Thereaction time may be generally from 30 minutes to 7 days, preferablyfrom 3 hours to 2 days.

Preferably, the reaction of a compound of formula (Ia) and a compound offormula (IIa) is effected in the presence of a base. The base includes,for example, an inorganic base such as sodium hydroxide, potassiumhydroxide, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, cesium carbonate; and an organic base such as triethylamine,diisopropylamine. The amount of the base to be used may be generallyfrom 0.5 mols to 5 mols, preferably from 0.7 mols to 3 mols relative to1 mol of the compound of formula (a).

In the reaction of a compound of formula (Ia) and a compound of formula(IIa), the amino group, the imino group, the hydroxyl group, thecarboxyl group, the oxo group or the carbonyl group in the compound offormula (Ia) or in Y^(1p) in formula (IIa) may be protected with aprotective group, and then the reaction may be effected, and, after thereaction, the protective group may be removed. The protective group forsuch an amino group or an imino group may be any one having its ownfunction, including, for example, an aralkyl group such as a benzylgroup, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, ano-nitrobenzyl group, a p-nitrobenzyl group, a benzhydryl group, a tritylgroup; a lower alkanoyl group such as a formyl group, an acetyl group, apropionyl group, a butyryl group, a pivaloyl group; a benzoyl group; anarylalkanyl group such as a phenylacetyl group, a phenoxyacetyl group; alower alkoxycarbonyl group such as a methoxycarbonyl group, anethoxycarbonyl group, a propyloxycarbonyl group, a tert-butoxycarbonylgroup; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, ap-nitrobenzyloxycarbonyl group, a phenethyloxycarbonyl group; a loweralkylsilyl group such as a trimethylsilyl group, atert-butyldimethylsilyl group; a tetrahydropyranyl group; atrimethylsilylethoxymethyl group; a lower alkylsulfonyl group such as amethylsulfonyl group, an ethylsulfonyl group; an arylsulfonyl group suchas a benzenesulfonyl group, a toluenesulfonyl group. Preferredparticularly are an acetyl group, a benzoyl group, a tert-butoxycarbonylgroup, a trimethylsilylethoxymethyl group, a methylsulfonyl group andthe like.

The protective group for the hydroxyl group not participating in thereaction, in the compound of formula (a) or in Y^(1p) in formula (IIa),may be any one having its own function. For example, it includes a loweralkyl group such as a methyl group, an ethyl group, a propyl group, anisopropyl group, a tert-butyl group; a lower alkylsilyl group such as atrimethylsilyl group, a tert-butyldimethylsilyl group; a loweralkoxymethyl group such as a methoxymethyl group, a2-methoxyethoxymethyl group; a tetrahydropyranyl group; atrimethylsilylethoxymethyl group; an aralkyl group such as a benzylgroup, a p-methoxybenzyl group, a 2,3-dimethoxybenzyl group, ano-nitrobenzyl group, a p-nitrobenzyl group, a trityl group; an acylgroup such as a formyl group, an acetyl group. Preferred particularlyare a methyl group, a methoxymethyl group, a tetrahydropyranyl group, atrityl group, a trimethylsilylethoxymethyl group, atert-butyldimethylsilyl group, an acetyl group and the like.

The protective group for the carboxyl group not participating in thereaction, in the compound of formula (a or in Y^(1p) in formula (IIa),may be any one having its own function. For example, it includes a loweralkyl group such as a methyl group, an ethyl group, a propyl group, anisopropyl group, a tert-butyl group; a halo-lower alkyl group such as a2,2,2-trichloroethyl group; a lower alkenyl group such as a 2-propenylgroup; an aralkyl group such as a benzyl group, a p-methoxybenzyl group,a p-nitrobenzyl group, a benzhydryl group, a trityl group. Preferredparticularly are a methyl group, an ethyl group, a tert-butyl group, a2-propenyl group, a benzyl group, a p-methoxybenzyl group, a benzhydrylgroup and the like.

The protective group for the oxo group or the carbonyl group notparticipating in the reaction, in the compound of formula (Ia) or inY^(1p) in formula (IIa), may be any one having its own function. Forexample, it includes acetals and ketals such as ethylene ketal,trimethylene ketal, dimethyl ketal.

The compound of formula (Ib) thus obtained in the manner as above is,after purified or not purified, subjected to removal or conversion ofthe protective group when Y^(1p) in the formula has a protected aminogroup, hydroxyl group, carboxyl group, oxo group or carbonyl group,whereby the intended compound of formula (I-1) may be produced. Theremoval of the protective group may differ, depending on the type of theprotective group and on the stability of the intended product compound(I-1). For example, it may be attained through solvolysis with an acidor a base according to methods described in references (see ProtectiveGroups in Organic Synthesis written T. W. Green; published by John Wiley& Sons, 1981) or according to methods similar to these, for example,according to a method of reacting the product with from 0.01 mol to alarge excessive amount of an acid, preferably trifluoroacetic acid,formic acid or hydrochloric acid, or with an equimolar amount or a largeexcessive amount of a base, preferably potassium hydroxide or calciumhydroxide, or through chemical reduction with a metal hydride complex,or through catalytic reduction with a palladium-carbon catalyst or aRaney nickel catalyst or the like.

[Production Method 2]

A compound of a general formula (Ic):

[wherein X¹ and X² have the same meanings as X¹ and X² in formula (I);Y^(1p) has the same meaning as Y in a general formula (II), orrepresents a group corresponding to it but protected at the ammo group,the hydroxyl group or the carboxyl group therein; and L² represents aleaving group] is reacted with a compound of a formula (Id):

[wherein R¹, R² and X³ have the same meanings as R¹, R² and X³ informula (I)] under a basic condition or in the presence of a catalyst togive a compound of a general formula (Ie):

[wherein X¹, X² and Y^(1p) have the same meanings as X¹, X² and Y^(1p)in formula (Ic); X³, R¹ and R² have the same meanings as X³, R¹ and R²in formula (Id)], and optionally the protective group for the functionalgroup of Y^(1p) is removed or converted (e.g., for amine residueacylation, carboxylic acid residue amidation, alcohol residuealkylation) to thereby produce a compound of a general formula (I-2):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (Ie); and Y is a group derived from Y^(1p) in formula(Ie) by removing or converting the protective group for the functionalgroup of Y^(1p).

The introduction of a protective group to the functional group notparticipating in the reaction in the compounds or in Y^(1p), as well asthe removal and the conversion of the protective group after thereaction, and the treatment after the reaction may be attained accordingto the methods described for the Production Method 1.

[Production Method 3]

A compound of a general formula (If):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (I); Met represents a metal atom-containing atomicgroup] is reacted with a compound of a general formula (Ig):

Y^(1p)-L₂  (IIb)

[wherein Y^(1p) has the same meaning as Yin formula (II), or representsa group corresponding to it but protected at the amino group, thehydroxyl group or the carboxyl group therein; and L² represents anordinary leaving group], in the presence of a catalyst to give acompound of a general formula (Ig):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (If); and Y^(1p) has the same meaning as Y^(1p) informula (IIb)], and optionally the protective group for the functionalgroup of Y^(1p) is removed or converted (e.g., for amine residueacylation, carboxylic acid residue amidation, alcohol residuealkylation) to thereby produce a compound of a general formula (I-3):

[wherein X¹, X², X³, R¹ and R² have the same meanings as X¹, X², X³, R¹and R² in formula (Ig); and Y is a group derived from Y^(1p) in formula(Ig) by removing or converting the protective group for the functionalgroup of Y^(1p)].

The starting substances, compounds of formula (Ia) and (IIa), as well ascompounds of formula (Ic) and (Id), and compounds of formula (IIb) thatare used in the above-mentioned production methods may be prepared inknown methods or according to such known methods, or according to themethods described in Examples and Reference Examples herein, optionallyby suitably combining them.

The compounds of formula (If) that are the starting substance for use inthe above-mentioned production methods may be prepared as follows:

1) Reaction of a compound of formula (Ia) with a lower alkyl metal,2) Reaction of a compound of formula (Ia) with a lower alkyl metalfollowed by further reaction of the intermediate with a metal halide oran ester,3) Reaction of a compound of formula (Ia) with, for example, abis(tri-lower alkyl tin) or bis(boronate) in the presence of a catalyst.

The compounds of formula (Ib), (I-1), (Ie), (I-2), (Ig) or (I-3)produced in the above-mentioned production methods may be readilyisolated and purified in any ordinary separation method. The methodincludes, for example, solvent extraction, recrystallization, columnchromatography, preparative thin-layer chromatography.

Pharmaceutically-acceptable salts of the piperidine derivatives offormula (I) may be produced by a method of adding an acid or a base tothe piperidine derivative obtained in any of the above-mentionedmethods. For producing acid-addition salts of the piperidine derivative,for example, a hydrohalic acid such as hydrochloric acid, hydrofluoricacid, hydrobromic acid or hydroiodic acid, or an inorganic acid such asnitric acid, perchloric acid, sulfuric acid, phosphoric acid or carbonicacid, or a lower alkylsulfonic acid such as methanesulfonic acid,trifluoromethanesulfonic acid or ethanesulfonic acid, or an arylsulfonicacid such as benzenesulfonic acid or p-toluenesulfonic acid, or anorganic acid such as fumaric acid, succinic acid, citric acid, tartaricacid, oxalic acid, maleic acid, or any other organic acid such as anamino acid, e.g., glutamic acid or aspartic acid may be added to thepiperidine derivative. For producing acid-addition salts of thepiperidine derivative, for example, an alkali metal salt with sodium orpotassium, or an alkaline earth metal salt with calcium or magnesium, oran ammonium salt, or an organic base such as guanidine, triethylamine ordicyclohexylamine may be added to the piperidine derivative.

Esters of the piperidine derivative of formula (I) may also be producedin known methods. On the contrary, the pharmaceutically-acceptable saltsor esters of the piperidine derivative of formula (I) may be convertedinto the corresponding free piperidine derivatives by converting esteraccording to ordinary methods.

The piperidine derivative of formula (I) or itspharmaceutically-acceptable salt significantly inhibits histamine-H3receptor-expressing cells from bonding to Nα-methylhistamine (histamineanalogue), and therefore effectively acts as a histamine-H3 receptorantagonist or inverse-agonist. In addition, it significantly detractsfrom the in-vitro action of R-α-methylhistamine (selective agonist).

Not specifically defined, the histamine-H3 receptor antagonist orinverse-agonist of the invention may comprise, as the active ingredientthereof, a piperidine derivative of formula (I) or itspharmaceutically-acceptable salt, and its administration route may beeither orally or parenterally. It may be formulated into a preparationsuitable for its administration, and may be adminstered. Thehistamine-H3 receptor antagonist or inverse-agonist is effective, forexample, for metabolic system diseases such as obesity, diabetes,hormone secretion disorder, hyperlipemia, gout, fatty liver, circulatorysystem diseases such as stenocardia, acute/congestive cardiacinsufficiency, cardiac infarction, coronary arteriosclerosis,hypertension, nephropathy, electrolyte metabolism disorder, and centraland peripheral nervous system diseases such as bulimia, emotionaldisorder, melancholia, anxiety, epilepsy, delirium, dementia,shinzophrenia, attention deficit/hyperactivity disorder, memorydisorder, Alzheimer's disease, Parkinson's disease, sleep disorder,recognition disorder, motion disorder, paresthesia, dysosmia, epilepsy,morphine resistance, narcotic dependency, alcoholic dependency.

In clinical use of the piperidine derivatives of formula (I) or theirpharmaceutically-acceptable salts of the invention,pharmaceutically-acceptable additives may be added thereto to formulatevarious preparations in accordance with the intended administrationroute thereof and the preparations may be administered. Variousadditives generally used in the field of pharmaceutical compositions maybe used herein, including, for example, gelatin, lactose, white sugar,titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose, corn starch, microcrystalline wax,white petrolatum, magnesium metasilicate aluminate, anhydrous calciumphosphate, citric acid, trisodium citrate, hydroxypropyl cellulose,sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acidester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone,magnesium stearate, light silicic acid anhydride, talc, vegetable oil,benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol,cyclodextrin, and hydroxypropylcyclodextrin.

Combined with such additives, the compound of the invention may beformulated into various forms of preparations, for example, solidpreparations such as tablets, capsules, granules, powders andsuppositories; and liquid preparations such as syrups, elixirs andinjections. These preparations can be produced in any method known inthe filed of pharmaceutical compositions. The liquid preparations may bein such a form that is dissolved or suspended in water or in any othersuitable medium before use. Especially for injections, the preparationmay be dissolved or suspended, if desired, in a physiological saline orglucose solution, and a buffer and a preservative may be added thereto.The preparations may contain the piperidine derivative of formula (I) orits pharmaceutically-acceptable salt of the invention in an amount offrom 1.0 to 100% by weight, preferably from 1.0 to 60% by weight of thetotal medicines.

When the piperidine derivatives of formula (I) or theirpharmaceutically-acceptable salts of the invention are used in clinicalsites, then the dose and the administration frequency thereof may varydepending on the sex, the age, the body weight and the condition of thepatient and on the type and the scope of the treatment of the patient.In oral administration, in general, the dose may be from 0.01 to 100mg/kg-adult/day, preferably from 0.03 to 1 mg/kg-adult/day, and it maybe administered all at a time or may be administered in a few times asdivided into a few portions. In parenteral administration, its dose maybe from 0.001 to 10 mg/kg-adult/day, preferably from 0.001 to 0.1mg/kg-adult/day, and it may be administered all at a time or may beadministered in a few times as divided into a few portions. Not limitedto the dose ranges as above, any ordinary physicians, veterinarians andclinicians may readily determine the effective dose necessary forretarding, inhibiting or stopping the development of diseases.

In their use, the piperidine derivatives of formula (I) and theirpharmaceutically-acceptable salts of the invention may be combined withone or more other agents effective for treatment of metabolic disordersand/or dietary disorders, circulatory system diseases, and central orperipheral nervous system diseases. The individual ingredients to becombined may be administered at the same time or at different times orsuccessively in order during the treatment period, either as onepreparation or as divided different preparations. The ingredientsinclude, for example, co-medicines effective for hypertension,obesity-related hypertension, hypertension-related disorders,cardiomegaly, left ventricle hypertrophy, metabolic disorders, obesity,obesity-related disorders. In other words, the compounds of theinvention may be combined with any other co-medicines for so-calledcombination therapy.

When one or more such co-medicines are combined with a piperidinederivative of formula (I) or its pharmaceutically-acceptable salt of theinvention for such combination therapy and when they are administeredall at a time, then they may be in the form of a pharmaceuticalcomposition for single administration. On the other hand, when they areadministered at the same time or differently or successively, then theymay be in different packages. The dose of the co-medicine may depend onthe clinical use thereof, and may be suitably determined in accordancewith the administration object, the administration route, the diseasesand the combination. The form of the co-medicine for administration isnot specifically defined, and it may be combined with the piperidinederivative of formula (I) or its pharmaceutically-acceptable salt of theinvention when they are administered. The administration withco-medicines mode includes, for example, the following: (1) A compoundof the invention is combined with a co-medicine to give a singlepreparation for single administration; (2) a compound of the inventionand a co-medicine are separately formulated into different twopreparations, and the two preparations are simultaneously administeredin one administration route; (3) a compound of the invention and aco-medicine are separately formulated into different two preparations,and they are administered at different times in one and the sameadministration route; (4) a compound of the invention and a co-medicineare separately formulated into different two preparations, and they areadministered at the same time in two different administration routes;(5) a compound of the invention and a co-medicine are separatelyformulated into different two preparations, and they are administered atdifferent times in different administration routes (for example, acompound of the invention and a co-medicine are administered in thatorder, or in an order contrary to this). The blend ratio of thepiperidine derivative of formula (I) or its pharmaceutically-acceptablesalt of the invention and the co-medicine may be suitably determineddepending on the administration object, the administration route, andthe disease for the administration.

Therapeutical medicines for diabetes that may be used for suchco-medicines include, for example 1) PPAR-γ agonists such as glitazones[e.g., ciglitazone, darglitazone, englitazone, isaglitazone, MCC-555],pioglitazone, rosiglitazone, troglitazone, BRL49653, CLX-0921, 5-BTZD,GW-0207, LG-100641, LY-300512; 2) biguanides such as metformin,buformin, phenformin; 3) protein tyrosine phosphatase 1B inhibitors; 4)sulfonylureas such as acetohexamide, chlorpropamide, diabinese,glibenclamide, glipizide, glyburide, glimepiride, gliclazide,glipentide, gliquidone, glisolamide, trazamide, tolubutamide; 5)meglitinides such as repaglinide, nateglinide; 6) α-glucoside hydrolaseinhibitors such as acarbose, adiposine, camiglibose, emiglitate,miglitol, voglibose, pradimicin-Q, salbostatin, CKD-711, MDL-25,673,MDL-73,945, MOR14; 7) α-amylase inhibitors such as tendamistat,trestatin, A13688; 8) insulin secretion promoters such as linogliride,A-4166; 9) fatty acid oxidation inhibitors such as clomoxir, etomoxir,10) A2 antagonists such as midaglizole, isaglidole, deriglidole,idazoxan, earoxan, fluparoxan; 11) insulin or insulin mimetix such asbiota, LP-100, novalapid, insulin determir, insulin lispro, insulinglargine, insulin zinc, Lys-Pro-insulin, GLP-1 (73-7), GLP1 amide(7-36); 12) non-thiazolidinediones such as JT-501, farglitazar, 13)PPARα/γ co-agonists such as CLX-0940, GW-1536, GW-1929, GW-2433,KPR-297, L-796449, L-90, SB219994.

Therapeutical medicines for hyperlipemia that may be used for theabove-mentioned co-medicines include, for example, 1) bile acidabsorption promoters such as cholesterylamine, colesevelem, colestipol,crosslinked dextran dialkylaminoalkyl derivatives, Colestid®,LoCholest®, Questran®; 2) HMG-CoA reductase inhibitors such asatorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, rosuvastatin, simvastatin, ZD4522; 3) HMG-CoA synthaseinhibitors; 4) cholesterol absorption inhibitors such as snatol ester,β-sitosterol, sterol glucoside, ezetimibe; 5) acyl-coenzyme Acholesterol transacylase inhibitors such as avasimibe, eflucimibe,KY-505, SMP-709; 6) CETP inhibitors such as JTT705, torcetrapib,CP532632, BAY-63-2149, SC-591, SC-795; 7) squalane synthesis inhibitors;8) antioxidants such as probucol; 9) PPARα agonists such asbeclofibrate, benzafibrate, syprofibrate, clofibrate, etofibrate,fenofibrate, gemcabene, gemfibrozil, GW-7647, BM-170744, LY-518674,fibric acid derivatives (e.g., Atromid®, Lopid®, Tricor®); 10) FXRreceptor antagonists such as GW4064, SR-103912; 11) LXR receptoragonists such as GW3965, T9013137, XTCO-179628; 12) lipoproteinsynthesis inhibitors such as niacin; 13) renin-angiotensin systeminhibitors; 14) microsome triglyceride transportation inhibitors; 15)bile acid reabsorption inhibitors such as BARA1453, SC435, PHA384640,S-435, AZD7706; 16) PPARδ agonists such as GW501516, GW590735; 17)triglyceride synthesis inhibitors; 18) MTTP inhibitors such as LAB687,CP346086; 19) low-density lipoprotein 20) squalane epoxidase inhibitors;21) platelet agglutination inhibitors; 22) 5-lipoxygenase activationprotein inhibitors such as MK-591.

Therapeutical medicines for hypertension that may be used for theabove-mentioned co-medicines include, for example, 1) thiazide diureticssuch as chlorothialidon, chlorothiazide, dichlorofenamide,hydrofluorothiazide, indapamide, hydrochlorothiazide; loop diureticssuch as bumetamide, ethacrynic acid, flosemide, tolusemide; sodiumdiuretics such as amiloride, triamteren, aldosterone antagonistdiuretics such as spironolactone, epilenone; 2), β-adrenaline blockerssuch as acebutolol, atenolol, betaxolol, bevantolol, bisoprolol,bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol,metaprolol, nadolol, nebivolol, penbutolol, pindolol, probanolol,sotalol, tartatolol, tilisolol, timolol; 3) calcium channel blockerssuch as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine,bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine,gallopamil, isradipine, lacidipine, lemildipine, lercanidipine,nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine,nitrendipine, manidipine, pranidipine, verapamil; 4) angiotensintransferase inhibitors such as benazepril, captopril cilazapril,delapril, enalapil, fosinopril, imidapril, rosinopril, moexipril,quinapril, quinapirat, ramipril, perindopril, periondopril, quanipril,spirapril, tenocapril, transolapril, zofenopril; 5) neutralendopeptidase inhibitors such as omapatrilat, cadoxatril, ecadotril,fosidotril, sampatrilat, AVE7688, ER4030; 6) encloserine antagonistssuch as tezosentan, A308165, YM62899; 7) vasodilators such ashydraladine, clonidine, minoxidil, nicotinyl alcohol; 8) angiotensin IIantagonists such as candesartan, eporsartan, inbesartan, rosartan,pratosartan, tasosartan, telmisartan, balsartan, EXP-3137, FH6828K,RNH6270; 9) α/β adrenaline blockers such as nipradilol, arotinolol,amoslalol; 10) αI blockers such as terazosin, urapidil, purazosin,bunazosine, trimazosin, doxazocin, naphthopidil, indolamin, WHIP164,XEN010; 11) α2 agonists such as lofexidine, tiamenidine, moxonidine,rilmenidine, guanabenz; 12) aldosterone inhibitors.

Anti-obesity medicines that may be used for the above-mentionedco-medicines include, for example, 1) 5HT (serotonin) transporterinhibitors such as paraxetin, fluoxetine, fenfluramine, fluvoxamine,sertraline, imipulamin; 2) norepinephrine transporter inhibitors such asGW320659, decipulamin, talsupramin, nomifensin; 3) cannabinoid-1receptor 1 (CB-1) antabonists/inverse-agonists such as limonabant(Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY-65-2520 (Bayer),SLV-318 (Sorbei), as well as compounds disclosed in U.S. Pat. No.5,532,237, U.S. Pat. No. 4,973,587, U.S. Pat. No. 5,013,837, U.S. Pat.No. 5,081,122, U.S. Pat. No. 5,112,820, U.S. Pat. No. 5,292,736, U.S.Pat. No. 5,624,941, U.S. Pat. No. 6,028,084, WO96/33159, WO98/33765,WO98/43636, WO98/43635, WO01/09120, WO01/96330, WO98/31227, WO98/41519,WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO01/58869,WO02/076949, WO01/64632, WO01/64633, WO01/64634, WO03/006007,WO03/007887, EP-658546; 4) glerin antagonists such as compoundsdisclosed in WO01/87355, WO02/08250; 5) histamine (H3)antagonists/inverse-agonists such as thioperamide,3-(1H-imidazol-4-yl)propyl-N-(pentenyl)carbonate, clobenpropit,iodofenpropit, imoproxyfen, GT2395, A331440, compounds disclosed inWO02/15905, O-[3-(1H-imidazol-4-yl)propanol]carbamate,piperazine-containing H3-receptor antagonists (Lazewska, D. et al.,Phrmazie, 56: 927-32 (2001), benzophenone derivatives Sasse, A. et al.,Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemister, S. et al., Pharmazie, 55: 83-6 (2000)),proxyfen derivatives (Sasse, A. et al., J. Med. Chem., 43: 3335-43(2000)); 6) MCH-1R antagonists such as T-226296 (Takeda), SNP-7941(Synaptic), other compounds disclosed in WO01/82925, WO01/87834,WO02/051809, WO02/06245, WO02/076929, WO02/076947, WO02/04433,WO02/51809, WO02/083134, WO02/094799, WO03/004027, JP-A-2001-226269; 7)MCH-2R agonists/antagonists; 8) NPY1 antagonists such as isopropyl3-chloro-5-(1-(6-[2-(5-ethyl-4-methyl-thiazol-2-yl)ethyl]-4-morpholinyl-4-yl-pyridin-2-ylamino)-ethyl)phenyl]carbamate,BIBP3226, BIB03304, LY-357897, CP-671906, GI-264879, and other compoundsdisclosed in U.S. Pat. No. 6,001,836, WO96/14307, WO01/23387,WO99/51600, WO01/85690, WO01/85098, WO01/85173, WO01/89528; 9) NPY5antagonists such as 152804, GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR235,208, FR226928, FR240662, FR252384, 1229U91,GI-264879A, CGP71683A, LY-377897, LY366377, PD-160170, SR-120526A,SR-120819A, JCF-104, H409/22, and other compounds disclosed in U.S. Pat.No. 6,140,354, U.S. Pat. No. 6,191,160, U.S. Pat. No. 6,258,837, U.S.Pat. No. 6,313,298, U.S. Pat. No. 6,337,332, U.S. Pat. No. 6,239,395,U.S. Pat. No. 340,683, U.S. Pat. No. 6,326,375, U.S. Pat. No. 6,329,395,U.S. Pat. No. 6,337,332, U.S. Pat. No. 6,335,345, EP-01010691,EP-01044970, WO97/19682, WO97/20820, WO97/20821, WO97/20822, WO97/20823,WO98/27063, WO0/107409, WO00/185714, WO0/185730, WO00/64880, WO00/68197,WO0/69849, WO01/09120, WO01/14376, WO01/85714, WO01/85730, WO01/07409,WO01/02379, WO01/02379, WO01/23388, WO01/23389, WO01/44201, WO01/62737,WO01/62738, WO01/09120, WO02/20488, WO02/22592, WO02/48152, WO02/49648,WO02/094789, and compounds disclosed in Norman et al., J. Med. Chem.,43:4288-4312 (2000); 10) reptins such as human recombinant reptin(PEG-OB, Hoffman La Roche), recombinant methionylreptin (Amgen); 11)reptin derivatives such as compounds disclosed in U.S. Pat. No.5,552,524, U.S. Pat. No. 5,552,523, U.S. Pat. No. 5,552,522, U.S. Pat.No. 5,521,283, WO96/23513, WO96/23514, WO96/23515, WO96/23516,WO96/23517, 96/23518, WO96/23519, WO96/23520; 12) opioid antagonistssuch as narmefen (Revex®), 3-methoxynartorexon, naroxon, nartolexon,compounds disclosed in WO00/21509; 13) aurexin antagonists such asSB-334867A, and other compounds disclosed in WO01/96302, WO01/68609,WO02/51232, WO02/51838, WO03/023561; 14) vonbesin receptor subtype-3agonists; 15) cholecistokinin A (CCK-A) agonists such as AR-R15849,GI-181771, JMV-180, A-71378, A-71623, SR-146131, and other compoundsdisclosed in U.S. Pat. No. 5,739,106; 16) CNTF (ciliary neurotrophicfactors) such as GI-181771 (Glaxo-Smith Kline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, PD149164 (Pfizer); 17) CNTFderivatives such as axokine (Regeneron), and other compounds disclosedin WO94/09134, WO98/22128, WO99/43813; 18) growth hormone secretionreceptor agonists such as NN703, hexarelin, MK-0677, SM-130686,CP424,391, L-692,429, L-163,255, and compounds disclosed in U.S. Pat.No. 6,358,951, US Patent Application Nos. 2002/049196, 2002/022637,WO01/56592, WO02/32888; 19) serotonin receptor-2C agonists such asBVT933, DPCA37215, IK264, PNU22394, WAY161503, R-1065, YN348, and othercompounds disclosed in U.S. Pat. No. 3,914,250, WO02/36596, WO02/48124,WO02/10169, WO01/66548, WO02/44152, WO02/51844, WO02/40456, WO02/40457;20) melanocholtin-3 receptor agonists; 21) melanocholtin-4 receptoragonists such as CHIR86036 (Chiron), ME-10142, ME-10145 (Melacure), andother compounds disclosed in WO99/64002, WO00/74679, WO01/991752,WO01/74844, WO01/70708, WO01/70337, WO01/91752, WO02/059095,WO02/059107, WO02/059108, WO02/059117, WO02/12166, WO02/11715,WO02/12178, WO02/15909, WO02/068387, WO02/068388, WO02/067869,WO03/007949, WO03/009847; 22) monoamine reabsorption inhibitors such ascibtramin (Meridia®/Recuctil®) and its salts, and other derivativesdisclosed in U.S. Pat. No. 4,476,680, U.S. Pat. No. 4,806,570, U.S. Pat.No. 5,436,272, US Patent Application No. 2002/0006964, WO01/27068,WO01/62341; 23) serotonin re-uptake inhibitors such as dexfenfluramine,fluoxetine, and other compounds disclosed in U.S. Pat. No. 6,365,633,WO01/27060, WO01/162341; 24) glucagon-like peptide-1 agonists; 25)topiramate (Topimax®); 26) phytopharm compound 57 (e.g., CP644,673); 27)acetyl CoA carboxylase-2 (ACC2) inhibitors; 28) β-adrenalin receptor-3agonists such as AD9677/TAK677 (Dai-Nippon Pharmaceutical/TakedaChemical), CL-316,243, SB418790, BRL-37344, L-796568, BMS-196085,BRL-35135A, CGP12177A, BTA-243, W427353, trecadrine, Zeneca D7114,SR59119A, and other compounds disclosed in U.S. Pat. No. 5,705,515, U.S.Pat. No. 5,451,677, WO01/74782, WO02/32898; 29) diacylglycerolacyltransferase-1 inhibitors; 30) diacylglycerol acyltransferase-2inhibitors, 31) fatty acid synthesis inhibitors such as carulenin, C75;32) phosphodiesterase inhibitors such as theofylline, pentoxifylline,zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram,cilomilast; 32) thyroid hormone-β, agonists such as KB-2611(KaroBioBMS), and other compounds disclosed in WO02/15845,JP-A-2000-256190; 33) phytanic acids such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoicacid (TTNPB), retinoic acid, and other compounds disclosed inWO99/00123; 34) acylestrogens such as oleoylestrone, and other compoundsdisclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001);35) glucocorticoid antagonists; 36) 11-βhydroxysteroid dehydrogenase-1inhibitors such as BVT3498, BVT2733, and other compounds disclosed inWO01/90091, WO01/90090, WO01/90092; 37) stearoyl-CoA desaturase-1inhibitors; 38) dipeptidyl peptidase-IV inhibitors such as isoleucinethiazolidine, valine pyrrolidine, NVP-DPP728, AF237, P93/01, TSL225,TMC-2A/2B/2C, FE999011, P9310/K364, VIP0177, SDZ274-444, and othercompounds disclosed in WO03/004498, WO03/004496, EP1258476, WO02/083128,WO02/062764, WO03/000250, WO03/002530, WO03/002531, WO03/002553,WO03/002539, WO03/000180, WO03/000181; 39) lipase inhibitors such astetrahydroliptatin (Orlistat/Xenical®), Triton WR1339, RHC80267,lipstatin, teasaponin, diethylumbelliferyl phosphate, FL-386,WAY-121898, Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactoneB, RHC80267, and other compounds disclosed in WO01/7094, U.S. Pat. No.4,598,089, U.S. Pat. No. 4,452,813, U.S. Pat. No. 5,512,565, U.S. Pat.No. 5,391,571, U.S. Pat. No. 5,602,151, U.S. Pat. No. 4,405,644, U.S.Pat. No. 4,189,438, U.S. Pat. No. 4,242,453; 39) fatty acid transporterinhibitors; 40) dicarboxylate transporter inhibitors; 41) glucosetransporter inhibitors; 42) phosphate transporter inhibitors.

Regarding the combination of the piperidine derivative of formula (I) orits pharmaceutically-acceptable salt of the invention with any of theabove-mentioned co-medicines, a combination with one or more selectedfrom a group consisting of medicines for diabetes and medicines forhyperlipemia is useful for prevention or remedy of metabolic disorders.In particular, a combination with a medicine for hypertension and amedicine for obesity along with a medicine for diabetes and/or amedicine for hyperlipemia is useful for prevention or remedy ofmetabolic disorders owing to the synergistic effect thereof.

Not specifically defined, the preventive or the remedy for metabolicdisorders of the invention may comprise a piperidine derivative offormula (I) or its pharmaceutically-acceptable salt as the activeingredient thereof

In formula (I), X¹ and X² independently resent a nitrogen atom or CH; X³presents O_(s)—(CH₂)_(m) (in which indicates 0 or 1; m indicates aninteger to make (m+s) 0 or 1 to 4); Y represents a group of a generalformula (II):

(in formula (II), j, k and l independently indicate 0 or 1; L¹represents a C1 to C4 alkylene group or a single bond, M represents anoxygen atom or a group of a genera formula (III):

(in formula (III), R⁰ represents a hydrogen atom or a C1 to C4 alkylgroup); Q₁ represents a linear or branched lower alkyl group, anoptionally-condensed C3 to C9 cycloalkyl group, a phenyl group, anaphthyl group, or an optionally-condensed 3-membered to 8-memberedheterocyclic group (the hetero ring may have from 1 to 3 hetero atomsselected from a group consisting of an oxygen atom, a sulfur atom and anitrogen atom), which is unsubstituted or has a substituent selectedfrom a group consisting of a cyano group, a hydroxyl group, a loweralkyl group (the lower alkyl group may be further substituted with ahydroxyl group, a halogen atom, an amino group, an aryl group or aheteroaryl group), a cycloalkyl group, a lower alkoxy group (the loweralkoxy group may be further substituted with a halogen atom), a halogenatom, a mono-lower alkylcarbamoyl group, a di-lower alkylcarbamoylgroup, a cycloalkyliminocarbamoyl group, a lactam ring, atrifluoromethyl group, a mono-lower alkylamino group, a di-loweralkylamino group and an alkanoyl group)); R¹ and R² independentlyrepresent a hydrogen atom, a halogen atom, a linear or branched loweralkyl group, a lower alkoxy group, or an acetyl group substituted with 2or 3 fluorine atoms; s indicates 0 or 1; m indicates an integer to make(m+s) 0 or 1 to 4.

The preventive or the remedy for metabolic system diseases of theinvention is preferably as follows: In formula (I), R¹ and R² arehydrogen atoms, m in X³ indicates an integer of from 1 to 3, s indicates0. Also preferably, in formula (II), Y is a group of the followinggeneral formula (IV):

Also preferably, in formula (IV), R³ is a hydrogen atom or a lower alkylgroup, R⁴ is a group of the following general formula (V):

[in formula (V), R⁵ represents a hydrogen atom, a lower alkyl group, aC3 to C8 cycloalkyl group, an aralkyl group, or a heteroaryl group; nindicates 0 or an integer of from 1 to 4].

Also preferably, in formula (V), R³ is a hydrogen atom, or a lower alkylgroup, and R⁴ is a group of the following general formula (VI):

—(CH₂)_(q)-A  (VI)

[in formula (VI), A represents an aryl group, a heteroaryl group, acondensed bicyclic group of a C4 to C7 cycloalkyl group and an arylgroup, or a condensed bicyclic group of a C4 to C7 cycloalkyl group anda heteroaryl group; q indicates 0 or an integer of from 1 to 3].

Also preferably, in formula (V), R³ and R⁴ form a nitrogen-containingheterocyclic group as integrated with the nitrogen atom to which theybond; more preferably, the nitrogen-containing heterocyclic group is amonocyclic group such as a piperidinyl group, a pyrrolidinyl group, anazetidinyl group, a homopiperidinyl group or a heptamethyleneiminylgroup, or a bicyclic group of such a monocyclic group and a C4 to C7cycloalkyl group, a phenyl group or a pyridyl group. Preferably in thiscase, X¹ and X² are both CH₂, or one of them is a nitrogen atom.

Also preferably, the preventive or remedy for metabolic system diseasesof the invention is as follows: Y in formula (II) is an aryl group or a5-membered or 6-membered heteroaryl group, which is unsubstituted orhas, in the ring thereof, 1 or 2 substituents selected from a groupconsisting of a lower alkyl group, a lower alkoxy group, a hydroxylgroup and a halogen atom. Preferably in this case, X¹ and X² are bothnitrogen atoms.

For the active ingredient of the preventive or remedy for metabolicsystem diseases of the invention, piperidine derivatives of formula (I)mentioned below are preferred.

-   N-methyl-N-(1-methylpiperidine-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (1),-   N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (2),-   N-methyl-N-(1-cyclobutylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (3),-   N-methyl-N-(1-cyclopentylpiperidine-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (4),-   N-methyl-N-(1-cyclohexylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (5),-   N-methyl-N-(1-cyclohexylmethylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (6),-   N-methyl-N-[(3R)-1-cyclopentylpyrrolidin-3-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (7),-   N-methyl-N-[(3S)-cyclopentylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (8),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (9),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (10),-   N-(pyridin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    trifluoroacetate (11),-   2-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroisoquinoline    (12),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroquinoline    (13),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-4-phenylpiperazine (14),-   N-methyl-N-[1-(pyrimidin-2-yl)piperidin-4-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (15),-   N-methyl-N-(thiophen-2-yl)methyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (16),-   N-methyl-N-phenethyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (17),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-3-3,4-difluorophenyl)pyrrolidine    (18),-   4-{4-(piperidin-1-yl)piperidin-1-yl]benzylpiperidin-1-yl (19),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]benzamide    (20),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(azetidin-1-yl)piperidin-1-yl]benzamide    (21),-   N-methyl-N-(1-methylpiperidin-4-yl)-5-[4-(piperidin-1-yl)piperidin-1-yl]pyridine-2-carboxamide    (22),-   N-methyl-N-(1-methylpiperidin-4-yl)    [4-(4,4-difluoropiperidin-1-yl)piperidin-1-yl]benzamide (23),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(4-cyanophenyl)pyrimidine    (24),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(3-pyridyl)pyrimidine (25),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3-trifluoromethylphenyl)pyrimidine    (26),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3,5-dichlorophenyl)pyrimidine    (27),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(2-naphthyl)pyrimidine (28),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-[4(pyrrolidin-1-ylcarbonyl)phenyl]pyrimidine    (29),-   1-[4-(piperidin-1-yl)piperidin-1-yl]-4-(3-pyridyl)benzene (30),-   1-piperidin-1-ylmethyl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzene    (31).

Not specifically defined, the preventive or the remedy for circulatorysystem diseases of the invention may comprise a piperidine derivative offormula (I) or its pharmaceutically-acceptable salt as the activeingredient thereof.

In formula (I), X¹ and X² independently represent a nitrogen atom or CH;X³ represents O_(s)—(CH₂)_(m) (in which indicates 0 or 1; m indicates aninteger to make (m+s) 0 or 1 to 4); Y represents a group of a generalformula (I):

(in formula (II), j, k and I independently indicate 0 or 1; L¹represents a C1 to C4 alkylene group or a single bond; M represents anoxygen atom or a group of a general formula (III):

(in formula (III), R⁰ represents a hydrogen atom or a C1 to C4 alkylgroup); Q₁ represents a linear or branched lower alkyl group, anoptionally-condensed C3 to C9 cycloalkyl group, a phenyl group, anaphthyl group, or an optionally-condensed 3-membered to 8-memberedheterocyclic group (the hetero ring may have from 1 to 3 hetero atomsselected from a group consisting of an oxygen atom, a sulfur atom and anitrogen atom), which is unsubstituted or has a substituent selectedfrom a group consisting of a cyano group, a hydroxyl group, a loweralkyl group (the lower alkyl group may be further substituted with ahydroxyl group, a halogen atom, an amino group, an aryl group or aheteroaryl group), a cycloalkyl group, a lower alkoxy group (the loweralkoxy group may be further substituted with a halogen atom), a halogenatom, a mono-lower alkylcarbamoyl group, a di-lower alkylcarbamoylgroup, a carbamoyl group, a cycloalkyliminocarbamoyl group, a lactamring, a trifluoromethyl group, a mono-lower alkylamino group, a di-loweralkylamino group and an alkanoyl group) (but excepting a case where Y isan alkoxycarbonyl group); R¹ and R² independently represent a hydrogenatom, a halogen atom, a linear or branched lower allyl group, a loweralkoxy group, or an acetyl group substituted with 2 or 3 fluorine atoms;s indicates 0 or 1; m indicates an integer to make (m+s) 0 or 1 to 4.

The preventive or the remedy for circulatory system diseases of theinvention is preferably as follows: In formula (I), R¹ and R² arehydrogen atoms, m in X³ indicates an integer of from 1 to 3, s indicates0. Also preferably, in formula (II), Y is a group of the followinggeneral formula (IV):

Also preferably, in formula (IV), R³ is a hydrogen atom or a lower alkylgroup, R⁴ is a group of the following general formula (V):

[in formula (V), R⁵ represents a hydrogen atom, a lower alkyl group, aC3 to C8 cycloalkyl group, an aralkyl group, or a heteroaryl group; nindicates 0 or an integer of from 1 to 4].

Also preferably, in formula (IV), R³ is a hydrogen atom, or a loweralkyl group, and R⁴ is a group of the following general formula (VI):

—(CH₂)_(q)-A  (VI)

[in formula (VI), A represents an aryl group, a heteroaryl group, acondensed bicyclic group of a C4 to C7 cycloalkyl group and an arylgroup, or a condensed bicyclic group of a C4 to C7 cycloalkyl group anda heteroaryl group; q indicates 0 or an integer of from 1 to 3].

Also preferably, in formula (IV), R³ and R⁴ form a nitrogen-containingheterocyclic group as integrated with the nitrogen atom to which theybond; more preferably, the nitrogen-containing heterocyclic group is amonocyclic group such as a piperidinyl group, a pyrrolidinyl group, anazetidinyl group, a homopiperidinyl group or a heptamethyleneiminylgroup, or a bicyclic group of such a monocyclic group and a C4 to C7cycloalkyl group, a phenyl group or a pyridyl group. Preferably in thiscase, X¹ and X² are both CH₂, or one of them is a nitrogen atom.

Also preferably, the preventive or remedy for circulatory systemdiseases of the invention is as follows: Y in formula (II) is an arylgroup or a 5-membered or 6-membered heteroaryl group, which isunsubstituted or has, in the ring thereof, 1 or 2 substituents selectedfrom a group consisting of a lower alkyl group, a lower alkoxy group, ahydroxyl group and a halogen atom. Preferably in this case, X¹ and X²are both nitrogen atoms.

For the active ingredient of the preventive or remedy for circulatorysystem diseases of the invention, piperidine derivatives of formula (I)mentioned below are preferred.

-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (1),-   N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (2),-   N-methyl-N-(1-cyclobutylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (3),-   N-methyl-N-(1-cyclopentylpiperidine-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (4),-   N-methyl-N-(1-cyclohexylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (5),-   N-methyl-N-(1-cyclohexylmethylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (6),-   N-methyl-N-[(3R)-1-cyclopentylpyrrolidin-3-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (7),-   N-methyl-N-[(3S)-1-cyclopentylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (8),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (9),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (10),-   N-(pyridin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    trifluoroacetate (11),-   2-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroisoquinoline    (12),-   1-{-4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroquinoline    (13),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-4-phenylpiperazine (14),-   N-methyl-N-[1-(pyrimidin-2-yl)piperidin-4-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (15),-   N-methyl-N-(thiophen-2-yl)methyl-4-[4(piperidin-1-yl)piperidin-1-yl]benzamide    (16),-   N-methyl-N-phenethyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (17),-   1-{4(piperidin-1-yl)piperidin-1-yl]benzoyl-3-(3,4-difluorophenyl)pyrrolidine    (18),-   4-{4-(piperidin-1-yl)piperidin-1-yl]benzylpiperidin-1-yl (19),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-pyrrolidin-1-ylpiperidin-1-yl]benzamide    (20),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-azetidin-1-yl)piperidin-1-yl]benzamide    (21),-   N-methyl-N-(1-methylpiperidin-4-yl)-5-[4-(piperidin-1-yl)piperidin-1-yl]pyridine-2-carboxamide    (22),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(4,4-difluoropiperidin-1-yl)piperidin-1-yl]benzamide    (23),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(4-cyanophenyl)pyrimidine    (24),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(3-pyridyl)pyrimidine (25),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3-trifluoromethylphenyl)pyrimidine    (26),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3,5-dichlorophenyl)pyrimidine    (27),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(2-naphthyl)pyrimidine (28),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-[4-(pyrrolidin-1-ylcarbonyl)phenyl]pyrimidine    (29),-   1-[4-(piperidin-1-yl)piperidin-1-yl]-4-(3-pyridyl)benzene (30),-   1-piperidin-1-ylmethyl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzene    (31).

The preventive or remedy for circulatory system diseases of theinvention is effective especially for stenocardia, acute/congestivecardiac insufficiency, cardiac infarction, coronary arteriosclerosis,hypertension, nephropathy, sleep disorder and various diseasesaccompanied by sleep disorder such as idiopathic hypersomnia, repetitivehypersomnia, true hypersomnia, narcolepsy, sleep periodic acromotiondisorder, sleep apnea syndrome, circadian rhythm disorder, chronicfatigue syndrome, REM sleep disorder, senile insomnia, night workersleep insanitation, idiopathic insomnia, repetitive insomnia, trueinsomnia, or electrolyte metabolism disorder.

Not specifically defined, the preventive or remedy for central orperipheral nervous system diseases of the invention may comprise apiperidine derivative of formula (I) or its pharmaceutically-acceptablesalt as the active ingredient thereof.

In formula (I), X¹ and X² independently represent a nitrogen atom or CH;X³ represents O_(s)—(CH₂)_(m) (in which s indicates 0 or 1; m indicatesan integer to make (m+s) 0 or 1 to 4); Y represents a group of a generalformula (II):

(in formula (II), j, k and l independently indicate 0 or 1; L¹represents a C1 to C4 alkylene group or a single bond; M represents anoxygen atom or a group of a general formula (III):

(in formula (III), R⁰ represents a hydrogen atom or a C1 to C4 alkylgroup); Q₁ represents a linear or branched lower alkyl group, anoptionally-condensed C3 to C9 cycloalkyl group, a phenyl group, anaphthyl group, or an optionally-condensed 3-membered to 8-memberedheterocyclic group (the hetero ring may have from 1 to 3 hetero atomsselected from a group consisting of an oxygen atom, a sulfur atom and anitrogen atom), which is unsubstituted or has a substituent selectedfrom a group consisting of a cyano group, a hydroxyl group, a loweralkyl group (the lower alkyl group may be further substituted with ahydroxyl group, a halogen atom, an amino group, (an aryl group) or aheteroaryl group), a cycloalkyl group, a halogen atom, acycloalkyliminocarbamoyl group, a lactam ring and a trifluoromethylgroup) (but excepting a case where Y is an alkoxycarbonyl group); R¹ andR² independently represent a hydrogen atom, a halogen atom, a linear orbranched lower alkyl group, a lower alkoxy group, or an acetyl groupsubstituted with 2 or 3 fluorine atoms; s indicates 0 or 1; m indicatesan integer to make (m+s) 0 or 1 to 4.

Preferably, in formula (I), R¹ and R² are hydrogen atoms, m in X³indicates an integer of from 1 to 3, s indicates 0. Also preferably, informula (II), Y is a group of the following general formula (IV):

Also preferably, in formula (V), R³ is a hydrogen atom or a lower alkylgroup, R⁴ is a group of the following general formula (V):

[in formula (V), R¹ represents a hydrogen atom, a lower alkyl group, aC3 to C8 cycloalkyl group, an aralkyl group, or a heteroaryl group; nindicates 0 or an integer of from 1 to 4].

Also preferably, in formula (V), R³ is a hydrogen atom, or a lower alkylgroup, and R⁴ is a group of the following general formula (VI):

—(CH₂)_(q)-A  (VI)

[in formula (VI), A represents an aryl group, a heteroaryl group, acondensed bicyclic group of a C4 to C7 cycloalkyl group and an arylgroup, or a condensed bicyclic group of a C4 to C7 cycloalkyl group anda heteroaryl group; q indicates 0 or an integer of from 1 to 3].

Also preferably, in formula (IV), R³ and R⁴ form a nitrogen-containingheterocyclic group as integrated with the nitrogen atom to which theybond; more preferably, the nitrogen-containing heterocyclic group is amonocyclic group such as a piperidinyl group, a pyrrolidinyl group, anazetidinyl group, a homopiperidinyl group or a heptamethyleneiminylgroup, or a bicyclic group of such a monocyclic group and a C4 to C7cycloalkyl group, a phenyl group or a pyridyl group. Preferably in thiscase, X¹ and X² are both CH₂, or one of them is a nitrogen atom.

Also preferably, the preventive or remedy for central or peripheralnervous system diseases of the invention is as follows: Y in formula(II) is an aryl group or a 5-membered or 6-membered heteroaryl group,which is unsubstituted or has, in the ring thereof, 1 or 2 substituentsselected from a group consisting of a lower alkyl group, a lower alkoxygroup, a hydroxyl group and a halogen atom. Preferably in this case, X¹and X² are both nitrogen atoms.

For the active ingredient of the preventive or remedy for central orperipheral nervous system diseases of the invention, piperidinederivatives of formula (I) mentioned below are preferred.

-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (1),-   N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (2),-   N-methyl-N-(1-cyclobutylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (3),-   N-methyl-N-(1-cyclopentylpiperidine-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (4),-   N-methyl-N-(1-cyclohexylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (5),-   N-methyl-N-(1-cyclohexylmethylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (6),-   N-methyl-N-[(3R)-1-cyclopentylpyrrolidin-3-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (7),-   N-methyl-N-[(3S)-1-cyclopentylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (8),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (9),-   N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (10),-   N-(pyridin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    trifluoroacetate (11),-   2-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroisoquinoline    (12),-   1-{-4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroquinoline    (13),-   1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-4-phenylpiperazine (14),-   N-methyl-N-[1-(pyrimidin-2-yl)piperidin-4-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (15),-   N-methyl-N-(thiophen-2-yl)methyl-4-[4(piperidin-1-yl)piperidin-1-yl]benzamide    (16),-   N-methyl-N-phenethyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide    (17),-   1-{4(piperidin-1-yl)piperidin-1-yl]benzoyl-3-(3,4-difluorophenyl)pyrrolidine    (18),-   4-{4-(piperidin-1-yl)piperidin-1-yl]benzylpiperidin-1-yl (19),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-pyrrolidin-1-ylpiperidin-1-yl]benzamide    (20),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-azetidin-1-yl)piperidin-1-yl]benzamide    (21),-   N-methyl-N-(1-methylpiperidin-4-yl)-5-[4-(piperidin-1-yl)piperidin-1-yl]pyridine-2-carboxamide    (22),-   N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(4,4-difluoropiperidin-1-yl)piperidin-1-yl]benzamide    (23),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(4-cyanophenyl)pyrimidine    (24),-   2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(3-pyridyl)pyrimidine (25),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3-trifluoromethylphenyl)pyrimidine    (26),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3,5-dichlorophenyl)pyrimidine    (27),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(2-naphthyl)pyrimidine (28),-   2-[4-(piperidin-1-yl)piperidin-1-yl]-5-[4-(pyrrolidin-1-ylcarbonyl)phenyl]pyrimidine    (29),-   1-[4-(piperidin-1-yl)piperidin-1-yl]-4-(3-pyridyl)benzene (30),-   1-(piperidin-1-ylmethyl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzene    (31).

The preventive or remedy for central and peripheral nervous systemdiseases of the invention is effective especially for bulimia, emotionaldisorder, melancholia, anxiety, epilepsy, delirium, dementia,shinzophrenia, attention deficit/hyperactivity disorder, memorydisorder, Alzheimer's disease, Parkinson's disease, sleep disorder,various diseases accompanied by sleep disorder such as idiopathichypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleepperiodic acromotion disorder, sleep apnea syndrome, circadian rhythmdisorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia,night worker sleep insanitation, idiopathic insomnia, repetitiveinsomnia, true insomnia, recognition disorder, motion disorder,paresthesia, dysosmia, epilepsy, morphine resistance, narcoticdependency, alcoholic dependency.

The invention is described more concretely with reference to thefollowing Formulation Examples and Production Examples, which, however,do not restrict the invention.

For thin-layer chromatography of compounds, used was a plate ofSilicagel 60F₂₄₅ (Merck); and for detection, used was a UV detector.Wakogel® C-300 (Wako Pure Chemicals) was used for the column silica gel;and LC-SORB® SP-B-ODS (Chemco) or YMCGEL® ODS-AQ 120-S50 (YamamuraChemical Laboratories) was for the reversed-phase column silica gel.

Mass spectrum was determined according to an electrospray ionization (ESprocess, using QuattroII (Micromass).

Example 1 Production of Piperidine Derivatives Compound 1:N-methyl-N-(1-methylpiperidinyl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

At room temperature, 1-methyl(4-methylamino)piperidine (0.056 ml, 0.38mmols), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (121 mg, 0.32 mmols) and diisopropylethylamine (0.17ml, 0.96 mmols) were added to a dimethylformamide solution (1.0 ml) of4-[(4-piperidin-1-yl)piperidin-1-yl]benzoic acid hydrochloride (103 mg,0.32 mmols) obtained in Reference Example 1, and s in a nitrogenatmosphere at room temperature for 14 hours. The reaction solution wasextracted with ethyl acetate, the organic layer was washed with water,saturated sodium bicarbonate solution and saturated saline solution inthe order, dried with anhydrous magnesium sulfate, and thenconcentrated. The residue was purified through preparative thin-layerchromatography (chloroform/methanol/aqueous ammonia=10/1/0.1) to obtainthe entitled compound (56 mg, 44%).

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.43-2.07 (18H, m), 2.24-2.31 (3H, m),2.50-2.70 (4H, m), 2.72-2.82 (2H, m), 2.86-2.96 (5H, m), 3.79-3.87 (2H,m), 6.87 (2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.8 Hz);

Mass spectrum (ESI): 399 (M+H)

The following compounds 2 to 23 were produced in the same productionmethod as that for the compound 1, or according to the method, or incombination of the method with an ordinary method.

Compound 2:N-(1-methylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however, 1-methyl-4-aminopiperidinewas used in place of 1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.41-1.78 (10H, m), 1.88-1.96 (2H, m),1.99-2.06 (2H, m), 2.11-2.20 (2H, m), 2.29 (3H, s), 2.41-2.58 (5H, m),2.74-2.85 (4H, m), 3.83-3.90 (2H, m), 3.92-4.02 (1H, m), 5.80 (1H, brd,J=7.6 Hz), 6.86 (2H, d, J=8.8 Hz), 7.62 (2H, d, J=8.8 Hz);

Mass spectrum (ES): 385 (M+H)

Compound 3:N-methyl-N-(1-cyclobutylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-cyclobutyl(4-methylamino)piperidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.41-2.07 (2H, m), 2.40-2.59 (6H, m),2.62-2.80 (4H, m), 2.83-2.90 (2H, m), 2.90 (3H, s), 3.79-3.86 (2H, m),6.87 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz);

Mass spectrum (ESI): 439 (M+H)

Compound 4:N-methyl-N-(1-cyclopentylpiperidine-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-cyclopentyl(4-methylamino)piperidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.33-2.10 (25H, m), 2.40-2.58 (6H, m),2.72-2.80 (2H, m), 2.90 (3H, s), 3.04-3.14 (2H, m), 3.79-3.86 (2H, m),6.87 (2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.8 Hz);

Mass spectrum (ESI): 453 (M+H)

Compound 5:N-methyl-N-(1-cyclohexylpiperidin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-cyclohexyl(4-methylamino)piperidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.00-1.30 (6H, m), 1.40-1.49 (2H, m),1.56-1.1.95 (19H, m), 2.24-2.35 (1H, m), 2.38-247 (1H, m), 2.49-2.57(4H, m), 2.71-2.80 (2H, m), 2.86-3.00 (2H, m), 2.90 (3H, s), 3.79-3.86(2H, m), 6.87 (2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.8 Hz);

Mass spectrum (ESI): 467 (M+H)

Compound 6:N-methyl-N-(1-cyclohexylmethylpiperidin-4-yl)-4-[4-(piperidin-1-ylpiperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-cyclohexylmethyl(4-methylamino)piperidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 0.78-0.91 (2H, m), 1.05-1.28 (4H, m),1.33-1.49 (4H, m), 1.52-1.95 (20H, m), 2.02-2.12 (2H, m), 2.38-2.60 (4H,m), 2.68-2.80 (2H, m), 2.82-2.97 (1H, m), 2.90 (3H, s), 3.77-3.86 (2H,m), 6.87 (2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.8 Hz);

Mass spectrum SI): 481 (M+H)

Compound 7:N-methyl-N-[(3R)-1-cyclopentylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-cyclopentyl((3R)-methylamino)pyrrolidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.33-2.13 (20H, m), 2.32-2.78 (12H, m),3.01 (3H, s), 3.77-3.84 (2H, m), 4.50-4.80 (1H, m), 6.86 (2H, d, J=8.4Hz), 7.27 (2H, d, J=8.4 Hz);

Mass spectrum (ESI): 439 (M+H)

Compound 8:N-methyl-N-[(3S)-1-cyclopentylpyrrolidin-3-yl)]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-cyclopentyl((3S)-methylamino)pyrrolidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.33-2.13 (20H, m), 2.32-2.78 (12H, m),3.01 (3H, s), 3.77-3.84 (2H, m), 4.50-4.80 (1H, m), 6.86 (2H, d, J=8.4Hz), 727 (2H, d, J=8.4 Hz);

Mass spectrum (ESI): 439 (M+H)

Compound 9:N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl]-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-benzyl((3R)methylamino)pyrrolidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.41-1.48 (2H, m), 1.55-1.74 (8H, m),1.86-1.95 (3H, m), 2.24-2.31 (1H, m), 2.38-2.58 (6H, m), 2.69-2.79 (3H,m), 2.81-2.88 (1H, m), 3.03 (3H, s), 3.45-3.50 (1H, m), 3.62-3.68 (1H,m), 3.78-3.85 (2H, m), 6.85 (2H, d, J=8.0 Hz), 7.20-7.30 (5H, m), 7.28(2H, d, J=8.0 Hz);

Mass spectrum (ESI): 461 (M+H)

Compound 10:N-methyl-N-[(3R)-1-benzylpyrrolidin-3-yl)]-4-[4(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,1-benzyl((3S)-methylamino)pyrrolidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.41-1.48 (2H, m), 1.55-1.74 (8H, m),1.86-1.95 (3H, m), 2.24-2.31 (1H, m), 2.38-2.58 (6H, m), 2.69-2.79 (3H,m), 2.81-2.88 (1H, m), 3.03 (3H, s), 3.45-3.50 (1H, m), 3.62-3.68 (1H,m), 3.78-3.85 (2H, m), 6.85 (2H, d, J=8.0 Hz), 7.20-7.30 (5H, m), 7.28(2H, d, J=8.0 Hz);

Mass spectrum (ESI): 461 (M+H)

Compound 11:N-(pyridin-4-yl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamidetrifluoroacetate

The compound was produced according to the same production method asthat for the compound 1, for which, however, 4-aminopyridine was used inplace of 1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CD₃OD, δ ppm): 1.47-1.60 (1H, m), 1.70-1.90 (5H, m),1.95-2.05 (2H, m), 2.16-2.25 (2H, m), 2.90-3.08 (4H, m), 3.32-3.48 (1H,m), 3.50-3.59 (2H, m), 4.13-4.21 (2H, m), 7.08 (2H, d, J=8.8 Hz), 7.94(2H, d, J=8.8 Hz), 8.29 (2H, d, J=8.4 Hz), 8.57 (2H, d, J=8.4 Hz);

Mass spectrum (ESI): 365 (M+H)

Compound 12:2-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroisoquinoline

The compound was produced according to the same production method asthat for the compound 1, for which, however,1,2,3,4-tetrahydroisoquinoline was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.41-1.51 (2H, m), 1.57-1.73 (6H, m),1.88-1.97 (2H, m), 2.41-2.61 (5H, m), 2.73-2.83 (2H, m), 2.88-2.97 (2H,m), 3.72-3.92 (4H, m), 4.70-4.83 (2H, m), 6.89 (2H, d, J=8.8 Hz),7.01-7.21 (4H, m), 7.37 (2H, d, J=8.8 Hz);

Mass spectrum (ES): 404 (M+1)

Compound 13:1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-1,2,3,4-tetrahydroquinoline

The compound was produced according to the same production method asthat for the compound 1, for which, however, 1,2,3,4-tetrahydroquinolinewas used in place of 1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.28-4.42 (25H, m), 6.68-7.77 (8H, m);

Mass spectrum (ESI): 404 (M+H)

Compound 14:1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-4-phenylpiperazine

The compound was produced according to the same production method asthat for the compound 1, for which, however, 4-phenylpiperazine was usedin place of 1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.40-1.50 (2H, m), 1.55-1.72 (6H, m),1.88-1.98 (2H, m), 2.40-2.60 (5H, m), 2.72-2.82 (2H, m), 3.10-3.23 (4H,m), 3.70-3.88 (6H, m), 6.81-6.98 (5H, m), 7.21-7.30 (2H, m), 7.35 (2H,d, J=8.8 Hz);

Mass spectrum (ESI): 433 (M+H)

Compound 15:N-methyl-N-[1-(pyrimidin-2-yl)piperidin-4-yl]-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however, 1(pyrimidin-2-yl)-4-methylaminopiperidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.40-1.50 (2H, m), 1.55-1.88 (11H, m),1.90-2.01 (2H, m), 2.41-2.63 (5H, m), 2.71-2.99 (4H, m), 2.87 (3H, s),3.80-3.90 (2H, m), 4.82-4.92 (2H, m), 6.46 (1H, t, J=4.8 Hz), 6.88 (2H,d, J=8.8 Hz), 7.31 (2H, d, J=8.8 Hz), 8.28 (2H, d, J=4.8 Hz);

Mass spectrum (ESI): 463 (M+H)

Compound 16:N-methyl-N-(thiophen-2-yl)methyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however,2-methylaminomethylthiophene was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.40-1.50 (2H, m), 1.57-1.72 (6H, m),1.88-1.97 (2H, m), 2.41-2.60 (5H, m), 2.70-2.80 (2H, m), 3.00 (3H, s),3.80-3.88 (2H, m), 4.70-4.81 (2H, m), 6.86 (2H, d, J=8.8 Hz), 6.92-7.00(2H, m), 7.21-7.28 (1H, m), 7.39 (2H, d, J=8.8 Hz);

Mass spectrum (ESI): 398 (M+H)

Compound 17:N-methyl-N-phenethyl-4-[4-(piperidin-1-yl)piperidin-1-yl]benzamide

The compound was produced according to the same production method asthat for the compound 1, for which, however, methylphenethylamine wasused in place of 1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.37-1.50 (2H, m), 1.52-2.72 (6H, m),1.79-1.99 (2H, m), 2.01-2.62 (6H, m), 2.66-2.80 (2H, m), 2.82-3.12 (4H,m), 3.43-3.72 (2H, m), 3.77-3.90 (2H, m), 6.80-6.92 (2H, m), 6.96-7.40(7H, m);

Mass spectrum (ESI): 406 (M+H)

Compound 18:1-{4-(piperidin-1-yl)piperidin-1-yl]benzoyl-3-(3,4-difluorophenyl)pyrrolidine

The compound was produced according to the same production method asthat for the compound 1, for which, however,3-(3,4-difluorophenyl)pyrrolidine was used in place of1-methyl(4-methylamino)piperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.40-1.50 (2H, m), 1.55-1.78 (6H, m),1.85-2.12 (4H, m), 2.20-2.68 (6H, m), 2.70-2.88 (2H, m), 3.22-4.15 (6H,m), 6.82-7.20 (5H, m), 7.43-7.59 (2H, m);

Mass spectrum (ESI): 454 (M+H)

Compound 19: 4-{-4-(piperidin-1-yl)piperidin-1-yl]benzylpiperidin-1-yl

The compound was produced according to the same production method asthat for the compound 1, for which, however, piperidine was used inplace of 1-methyl(4-methylaminopiperidine.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.16-2.10 (16H, m), 2.34-2.64 (5H, m),3.22-3.90 (4H, m), 6.87 (2H, d, J=7.2 Hz), 7.28 (2H, d, J=72 Hz);

Mass spectrum (ES: 356 (M+H)

Compound 20:N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]benzamide

Using 4-{4-pyrrolidin-1-yl)piperidin-1-yl}benzoic acid hydrochloridethat had been produced in the same production method as that for4-{4-(piperidin-1-yl)piperidin-1-yl}benzoic acid hydrochloride producedin Reference Example, or according to the method, or in combination ofthe method with an ordinary method, the entitled compound was producedaccording to the same production method as that for the compound 1.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.62-1.72 (4H, m), 1.79-2.04 (12H, m),2.16-2.24 (1H, m), 226 (3H, s), 2.59-2.66 (4H, m), 2.77-2.92 (3H, m),2.90 (3H, s), 3.72-3.79 (2H, m), 6.87 (2H, d, J=8.8 Hz), 7.28 (2H, d,J=8.8 Hz);

Mass spectrum (ESI): 385 (M+H)

Compound 21:N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(azetidin-1-yl)piperidin-1-yl]benzamide

Using 4-{4-(azetidin-1-yl)piperidin-1-yl}benzoic acid hydrochloride thathad been produced in the same production method as that for4-{4-(piperidin-1-yl)piperidin-1-yl}benzoic acid hydrochloride producedin Reference Example, or according to the method, or in combination ofthe method with an ordinary method, the entitled compound was producedaccording to the same production method as that for the compound 1.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.40-1.53 (2H, m), 1.57-2.35 (14H, m),2.29 (3H, s), 2.77-3.00 (3H, m), 2.90 (3H, s), 3.24-3.37 (3H, m),3.66-3.75 (2H, m), 6.60 (2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz);

Mass spectrum (ESI): 371 (M+H)

Compound 22:N-methyl-N-(1-methylpiperidin-4-yl)-5-[4-(piperidin-1-yl)piperidin-1-yl]pyridine-2-carboxamide

The entitled compound was produced by reacting1-methyl(4-methylamino)piperidine and5-{(4-piperidin-1-yl)piperidin-1-yl}pyridine-2-carboxylic acid.5-{4-(Piperidin-1-yl)piperidin-1-yl}pyridine-2-carboxylic acid wasproduced in the same production method as that for4-[4-(piperidin-1-yl)piperidin-1-yl}benzoic acid hydrochloride producedin Reference Example 1, or according to the method, or in combination ofthe method with an ordinary method.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.41-1.52 (2H, m), 1.57-1.73 (6H, m),1.75-2.02 (7H, m), 2.10-2.36 (4H, m), 2.42-2.53 (2H, m), 2.54 (3H, s),2.77-3.02 (3H, m), 2.98 (3H, s), 3.79-3.97 (3H, m), 4.46-4.58 (1H, m),7.18 (1H, dd, J=2.8, 8.8 Hz), 7.52 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=2.8Hz);

Mass spectrum (ESI): 400 (M+H)

Compound 23:N-methyl-N-(1-methylpiperidin-4-yl)-4-[4-(4,4-difluoropiperidin-1-yl)piperidin-1-yl]benzamide

The entitled compound was produced by reacting1-methyl(4-methylamino)piperidine and4-{(4,4-difluoropiperidin-1-yl)piperidin-1-yl}benzoic acidhydrochloride. 4-{(4,4-Difluoropiperidin-1-yl)piperidin-1-yl}benzoicacid hydrochloride was produced in the same production method as thatfor 4-[(4-piperidin-1-yl)piperidin-1-yl}benzoic acid hydrochlorideproduced in Reference Example 1, or according to the method, or incombination of the method with an ordinary method.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.56-1.76 (6H, m), 1.84-2.06 (9H, m),2.27 (3H, brs), 2.48-2.58 (1H, m), 2.64-2.70 (4H, m), 2.73-2.82 (2H, m),2.84-2.97 (2H, m), 2.90 (3H, s), 3.78-2.86 (2H, m), 6.87 (2H, d, J=8.4Hz), 7.28 (2H, d, J=8.4 Hz);

Mass spectrum (ESI): 435 (M+H)

Compound 24:2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(4-cyanophenyl)pyrimidine

1) Production of 2-[4-(piperidin-1-yl)piperidin-1-yl]-5-bromopyrimidine:

4-(Piperidin-1-yl)piperidine (342 mg, 2.03 mmols) and cesium carbonate(764 mg, 2.34 mmols) were added to DMF solution (10 ml) of2-chloro-5-bromopyrimidine (300 mg, 1.56 mmols), and stirred at roomtemperature for 16 hours. Water was added to the reaction mixture, whichwas then extracted with ethyl acetate. The organic layer was washed withsaturated saline solution, dried with anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The residue was purified throughsilica gel column chromatography (C-300, chloroform/methanol=100/3) toobtain the entitled compound (349 mg, 69%).

2) 1,2-Dimethoxyethane (2.0 ml) and aqueous 2 N sodium carbonatesolution (0.7 ml) were added to5-bromo-2-[4-(piperidin-1-yl)piperidin-1-yl]pyrimidine (169 mg, 0.52mmols), and then 4-cyanoboronic acid (95 mg, 0.65 mmols) andtetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmols) were addedthereto and stirred in a nitrogen atmosphere at 90° C. for 4 hours. Thereaction mixture was cooled to room temperature, and then extracted withethyl acetate. The organic layer was washed with saturated salinesolution, then dried with anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified through silica gelcolumn chromatography (C-300, chloroform/methanol=100/3) to obtain theentitled compound (113 mg, 62%).

¹H NMR (300 M CDCl₃, δ ppm): 1.38-1.66 (8H, m), 1.87-1.98 (2H, m),2.47-2.62 (5H, m), 2.86-2.97 (2H, m), 4.8-4.94 (2H, m), 7.57 (2H, d,J=8.3 Hz), 7.71 (1H, d, J=8.3 Hz), 8.51 (2H, s);

Mass spectrum (ESI): 348 (M+H)

The following compounds 25 to 30 were produced in the same productionmethod as that for the compound 24, or according to the method, or incombination of the method with an ordinary method.

Compound 25:2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(3-pyridyl)pyrimidine

The entitled compound was obtained by reacting5-bromo-2-{4-(piperidin-1-yl)piperidin-1-yl}pyrimidine that has beenobtained in the production process for the compound 24, withpyridine-3-boric acid.

¹H NMR (400 MHz, CDCl₃, δ ppm): 1.41-1.77 (9H, m), 1.91-2.00 (2H, m),2.51-2.65 (4H, m), 2.86-2.95 (2H, m), 4.84-4.91 (2H, m), 7.34 (1H, dd,J=4.8, 8.8 Hz), 7.74 (1H, d, J=8.0 Hz), 8.51 (2H, s), 8.55 (1H, d, J=4.8Hz), 8.73 (1H, s);

Mass spectrum (ESI): 324 (M+H)

Compound 26:2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3-trifluoromethylphenyl)pyrimidine

The entitled compound was obtained by reacting5-bromo-2-{4-(piperidin-1-yl)piperidin-1-yl}pyrimidine that has beenobtained in the production process for the compound 24, with3-trifluoromethyl-phenylboric acid.

¹H NMR (300 MHz, CDCl₃, δ ppm): 1.38-1.74 (9H, m), 1.89-2.00 (2H, m),2.49-2.64 (4H, m), 2.83-2.96 (2H, m), 4.82-4.93 (2H, m), 7.51-7.67 (3H,m), 7.70 (1H, s), 8.54 (2H, s);

Mass spectrum (ESI): 391 (M+H)

Compound 27:2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3,5-chlorophenyl)pyrimidine

The entitled compound was obtained by reacting5-bromo-2-{4-(piperidin-1-yl)piperidin-1-yl}pyrimidine that has beenobtained in the production process for the compound 24, with3,5-dichlorophenylboric acid.

¹H NMR (300 MHz, CDCl₃, δ ppm): 1.38-1.86 (8H, m), 1.87-2.00 (2H, m),2.48-2.64 (5H, m), 2.83-2.97 (2H, m), 4.83-4.94 (2H, m), 7.30 (1H, s),7.32 (2H, s), 8.47 (2H, s);

Mass spectrum (ESI): 391 (M+H)

Compound 28:2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(2-naphthyl)pyrimidine

The entitled compound was obtained by reacting5-bromo-2-{4-(piperidin-1-yl)piperidin-1-yl}pyrimidine that has beenobtained in the production process for the compound 24, withnaphtalene-2-boronic acid.

¹H NMR (300 MHz, CDCl₃, δ ppm): 1.40-1.67 (8H, m), 1.89-2.01 (2H, m),2.50-2.63 (5H, m), 2.86-2.98 (2H, m), 4.85-4.95 (2H, m), 7.43-7.54 (2H,m), 7.58-7.65 (1H, m), 7.83-7.95 (4H, m), 8.67 (2H, s);

Mass spectrum (ESI): 373 (M+H)

Compound 29:2-[4-(piperidin-1-yl)piperidin-1-yl]-5-[4-(pyrrolidin-1-ylcarbonyl)phenyl]pyrimidine

The entitled compound was obtained by reacting5-bromo-2-{4-(piperidin-1-yl)piperidin-1-yl}pyrimidine that has beenobtained in the production process for the compound 24, with4-(pyrrolidine-1-carbonyl)phenylboric acid.

¹H NMR (300 MHz, CDCl₃, δ ppm): 1.38-1.75 (9H, m), 1.83-2.04 (6H, m),2.46-2.63 (4H, m), 2.83-2.97 (2H, m), 3.43-3.52 (2H, m), 3.62-3.71 (2H,m), 4.82-4.93 (2H, m), 7.49 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz),8.55 (2H, s);

Mass spectrum (ESI): 420 (M+H)

Compound 30: 1-[4-(piperidin-1-yl)piperidin-1-yl]-4-(3-pyridyl)benzene

The entitled compound was obtained by reacting4-[4-(piperidin-1-yl)piperidin-1-yl]-bromobenzene and pyridine-3-boricacid. 4-[4-(Piperidin-1-yl)piperidin-1-yl]-bromobenzene was produced inthe same production method as that for5-bromo-2-[(4-piperidin-1-yl)piperidin-1-yl]pyrimidine produced inExample 24, or according to the method, or in combination of the methodwith an ordinary method.

¹H NMR (300 MHz, CDCl₃, δ ppm): 1.49-2.04 (9H, m), 2.61-2.84 (8H, m),3.83-3.87 (2H, m), 7.01 (2H, d, J=8.5 Hz), 7.26-7.34 (1H, m), 7.49 (2H,d, J=8.4 Hz), 7.81-7.84 (1H, m), 8.51 (1H, d, J=3.8 Hz), 8.81 (1H, d,J=2.3 Hz);

Mass spectrum (ESI): 322 (M+H)

Compound 31:1-(Piperidin-1-ylmethyl)-4-[4-(piperidin-1-yl)piperidin-1-yl]benzenedihydrochloride

The compound was obtained by reducing the compound 19 withlithiumaluminium hydride in an ordinary method.

¹H NMR (400 Hz, DMSO-d₆, δ ppm): 1.20-2.10 (16H, m), 2.10-2.30 (2H, m),2.62-3.00 (6H, m), 3.10-3.50 (5H, m), 3.70-4.42 (2H, m), 7.03 (2H, d,J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz);

Mass spectrum (ESI): 342 (M+H)

Reference Example 4-{4-(Piperidin-1-yl)piperidin-1-yl}benzoic AcidHydrochloride

1) Production of 4-[(4-piperidin-1-yl)piperidin-1-yl]benzonitrile:

Potassium carbonate (4.14 g, 30 mmols) and (4-piperidin-1-yl)piperidine(6.05 g, 36 mmols) were added to dimethylsulfoxide solution (10 ml) of4-fluorobenzonitrile (3.63 g, 30 mmols), and stirred at 95° C. for 3hours. The reaction mixture was cooled to room temperature, and pouredinto ice-water (300 ml) and stirred. The insoluble matter formed wastaken out through filtration, and dried to obtain the entitled compound(6.35 g, 81%).

2) Concentrated hydrochloric acid (10 ml) was added to4-[(4-piperidin-1-yl)piperidin-1-yl]benzonitrile (3.81 g, 14.1 mmols),and stirred at 130° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was taken out throughfiltration, washed with methanol/chloroform (2/1), and then dried toobtain the entitled compound (4.23 g, 92%).

[Preparation of Pharmaceutical Compositions] Formulation Example 1

10 parts of the compound of Example 1, 15 parts of heavy magnesium oxideand 75 parts of lactose were uniformly mixed to prepare a powdery orgranular preparation having a particle size of at most 350 μm. Thepreparation is encapsulated to give capsules.

Formulation Example 2

45 parts of the compound of Production Example 1, 15 parts of starch, 16parts of lactose, 21 parts of crystalline cellulose, 3 parts ofpolyvinyl alcohol and 30 parts of distilled water are uniformly mixed,then ground, granulated and dried, and then sieved to give a granularpreparation having a particle diameter of from 1410 to 177 μm.

Formulation Example 3

A granular preparation was prepared in the same manner as in FormulationExample 2. 96 parts of the granular preparation is mixed with 3 parts ofcalcium stearate, and shaped under compression into tablets having adiameter of 10 mm.

Formulation Example 4

90 parts of the granular preparation obtained according to the method ofFormulation Example 2 is mixed with 10 parts of crystalline celluloseand 3 parts of calcium stearate, and shaped under compression intotablets having a diameter of 8 mm. These are coated with a mixedsuspension of syrup gelatin and precipitated calcium carbonate to givesugar-coated tablets.

Example 2 Pharmaceutical Test

The usefulness of the histamine-H3 receptor antagonist containing apiperidine derivative of formula (I) of the invention as medicines wasproven by the following pharmaceutical test examples.

Pharmaceutical Test Example 1 Histamine Analogue-Binding Inhibition Test

A cDNA sequence coding for a human histamine-H3 receptor [seeInternational Laid-Open WO00/39164) was cloned with expression vectorspCR2.1, pEF1x (by Invitrogen) and pCI-neo (by Promega). The resultingexpression vector was transfected into host cells, HEK293 and CHO-K1(American Type Culture Collection), according to a cationic lipidprocess [see Proceedings of the National Academy of Sciences of theUnited States of America, Vol., 84, p. 7413 (1987)] to obtainhistamine-H3 receptor expression cells.

A membrane specimen prepared from the cells having expressed ahistamine-3 receptor was incubated in an assay buffer (50 mM Trisbuffer, pH 7.4) along with a test compound and 20,000 cpm of[³H]N^(a)-methylhistamine (by NEN) therein at 25° C. for 2 hours, andthen filtered through a glass filter GF/C. This was washed with 50 mMTris buffer (pH 7.4), and the radioactivity on the glass filter wasmeasured. The non-specific binding was determined in the presence of 10μM thioperamide (by Sigma), and the 50% inhibitory concentration (IC₅₀)of the test compound to specific N^(a)-methylhistamine binding wascalculated [see Molecular Pharmacology, Vol. 55, p. 1101 (1999)].

Pharmaceutical Test Example 2 Histamine Analogue-Binding Inhibition Test

A membrane specimen prepared from the cells having expressed ahistamine-H3 receptor was incubated in an assay buffer (50 mM Trisbuffer, 100 mM NaCl, 5 mM MgCl₂, pH 7.4) along with a test compound, 20nM R-methylhistamine (histamine analogue, by Sigma), 10 mM GDP(guanine-nucleotide diphosphate, by Sigma), 200 pM [³⁵S] GTPγS(guanine-nucleotide triphosphate analogue, by Amersham) and SPA resin(wheat germ agglutinin SPA beads, by Amersham) therein on a 96-welloptiplate (by Packard) at 25° C. for 3 hours and then centrifuged at3,000 rpm, and its activity was counted with Topcount (by Packard). Thenon-specific binding was determined in the presence of 10 μM GTPγS (bySigma), and the 50% inhibitory concentration (IC₅₀) of the test compoundto specific [³⁵S] GTPγS binding was calculated [see British Journal ofPharmacology, Vol. 135, p. 383 (2002)].

The results of Pharmaceutical Test Examples 1 and 2 are shown in Table6.

TABLE 6 Compound GTP g S IC50 Binding IC50 1

19 2

200 3

29 4

18 5

36 6

14 7

1.1 7.5 8

14 9

31 10

79 11

230 12

87 13

19 14

64 15

9.2 16

16 17

26 18

24 19

420 20

660 21

2400 22

180 23

670 24

61 25

160 26

2200 27

1700 28

1700 29

96 30

70 31

31 32

67 33

42 34

38 35

66 36

87 37

31 38

100 39

78 40

11

As is obvious from the results, the piperidine derivatives stronglyinhibited the binding of N^(a)-methylhistamine histamine analogue) tohistamine-H3 receptor.

INDUSTRIAL APPLICABILITY

The novel piperidine derivatives of the invention significantly inhibitsthe binding of Nα-methylhistamine (histamine analogue) to histamine-H3receptor-expressing cells, and they effectively act as a histamine-H3receptor antagonist or inverse-antagonist, and significantly inhibit thein-vitro action of R-α-methylhistamine (selective agonist). Thederivatives are effective as preventives or remedies for metabolicsystem diseases such as obesity, diabetes, hormone secretion disorder,hyperlipemia, gout, fatty liver, circulatory system diseases, forexample, stenocardia, acute/congestive cardiac insufficiency, cardiacinfarction, coronary arteriosclerosis, hypertension, nephropathy, sleepdisorder and various diseases accompanied by sleep disorder such asidiopathic hypersomnia, repetitive hypersomnia, true hypersomnia,narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome,circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder,senile insomnia, night worker sleep insanitation, idiopathic insomnia,repetitive insomnia, true insomnia, electrolyte metabolism disorder, andcentral and peripheral nervous system diseases such as bulimia,emotional disorder, melancholia, anxiety, epilepsy, delirium, dementia,shinzophrenia, attention deficit/hyperactivity disorder, memorydisorder, Alzheimer's disease, Parkinson's disease, sleep disorder,recognition disorder, motion disorder, paresthesia, dysosmia, epilepsy,morphine resistance, narcotic dependency, alcoholic dependency.

1-15. (canceled)
 16. A compound of the formula (I):

wherein: X¹ represents a nitrogen atom; X² represents a nitrogen atom;X³ represents —O_(s)—(CH₂)_(m)—, wherein s indicates 0 or 1, and mindicates an integer to make (m+s)=0, 1, 2, 3 or 4; R¹ and R²independently represent a hydrogen atom, a halogen atom, a linear orbranched lower alkyl group, a lower alkoxy group, or an acetyl groupsubstituted with 2 or 3 fluorine atoms; Y represents a phenyl group, anaphthyl group or a pyridyl group, which is unsubstituted or substitutedwith a substituent selected from a group consisting of a cyano group, ahydroxyl group, a lower alkyl group (the lower alkyl group may befurther substituted with a hydroxyl group, a halogen atom, an aminogroup, an aryl group or a heteroaryl group), a cycloalkyl group, a loweralkoxy group (the lower alkoxy group may be further substituted with ahalogen atom), a halogen atom, a mono-lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyl group, acycloalkyliminocarbamoyl group, a lactam ring, a trifluoromethyl group,a mono-lower alkylamino group, a di-lower alkylamino group and analkanoyl group; or a pharmaceutically-acceptable salt thereof.
 17. Thecompound of claim 16, wherein R¹ and R² are hydrogen atoms, X³ is—O_(s)—(CH₂)_(m)—, wherein s is 0 and m is an integer which is 1, 2 or3.
 18. The compound of claim 17, wherein X³ is —O_(s)—(CH₂)_(m)—,wherein s is 0 and m is an integer which is 2, to form a piperidinylgroup.
 19. The compound of claim 16, wherein Y is a phenyl group whichis unsubstituted or substituted with 1 or 2 substituents selected from agroup consisting of a cyano group, a trifluoromethyl group, a halogenatom and pyrrolidin-1-ylcarbonyl group.
 20. The compound of claim 16,wherein in Y is a pyridyl group.
 21. The compound of claim 16, whereinin Y is a naphthyl group.
 22. A compound which is selected from thegroup consisting of:2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(4-cyanophenyl)pyrimidine,2-[(4-piperidin-1-yl)piperidin-1-yl]-5-(3-pyridyl)pyrimidine,2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3-trifluoromethylphenyl)pyrimidine,2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(3,5-dichlorophenyl)pyrimidine,2-[4-(piperidin-1-yl)piperidin-1-yl]-5-(2-naphthyl)pyrimidine, and2-[4-(piperidin-1-yl)piperidin-1-yl]-5-[4-(pyrrolidin-1-ylcarbonyl)phenyl]pyrimidine,or a pharmaceutically-acceptable salt thereof.
 23. A pharmaceuticalcomposition which comprises an inert carrier and the compound of claim16, or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition which comprises an inert carrier and the compound of claim22, or a pharmaceutically acceptable salt thereof.
 25. A method fortreating a disease or disorder selected from the group consisting of:obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fattyliver; circulatory system disease, stenocardia, acute cardiacinsufficiency, congestive cardiac insufficiency, cardiac infarction,coronary arteriosclerosis, hypertension, nephropathy, sleep disorder,diseases accompanied by sleep disorder, idiopathic hypersomnia,repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodicacromotion disorder, sleep apnea syndrome, circadian rhythm disorder,chronic fatigue syndrome, REM sleep disorder, senile insomnia, nightworker sleep insanitation, idiopathic insomnia, repetitive insomnia,true insomnia, electrolyte metabolism disorder, central nervous systemdisease, peripheral nervous system disease, bulimia, emotional disorder,melancholia, anxiety, epilepsy, delirium, dementia, shinzophrenia,attention deficit/hyperactivity disorder, memory disorder, Alzheimer'sdisease, Parkinson's disease, sleep disorder, recognition disorder,motion disorder, paresthesia, dysomia, epilepsy, morphine resistance,narcotic dependency, and alcoholic dependency; in a mammalian patient inneed thereof which comprises administering to the patient atherapeutically effective amount of the compound of claim 16, or apharmaceutically acceptable salt thereof.